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1
Li, Lufeng, Wei Liu, Qi Mao, Denglu Zhou, Keqi Ai, Wei Zheng, Jihang Zhang, Lan Huang, Shangcheng Xu, and Xiaohui Zhao. "Klotho Ameliorates Vascular Calcification via Promoting Autophagy." Oxidative Medicine and Cellular Longevity 2022 (October 26, 2022): 1–14. http://dx.doi.org/10.1155/2022/7192507.
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Vascular calcification (VC) is regarded as a common feature of vascular aging. Klotho deficiency reportedly contributes to VC, which can be ameliorated by restoration of Klotho expression. However, the specific mechanisms involved remain unclear. Here, we investigated the role of autophagy in the process of Klotho-inhibiting VC. The clinical study results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells (MOVAS) under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification. This study is beneficial to exploring the underlying mechanisms of Klotho regulating VC, which has important guiding significance for future clinical studies in the treatment of VC.
2
Covic, Adrian, Mehmet Kanbay, Luminita Voroneanu, Faruk Turgut, Dragomir N. Serban, Ionela Lacramioara Serban, and David J. Goldsmith. "Vascular calcification in chronic kidney disease." Clinical Science 119, no. 3 (April 28, 2010): 111–21. http://dx.doi.org/10.1042/cs20090631.
Full textAbstract:
VC (vascular calcification) is highly prevalent in patients with CKD (chronic kidney disease), but its mechanism is multifactorial and incompletely understood. In addition to increased traditional risk factors, CKD patients also have a number of non-traditional cardiovascular risk factors, which may play a prominent role in the pathogenesis of arterial calcification, such as duration of dialysis and disorders of mineral metabolism. The transformation of vascular smooth muscle cells into chondrocytes or osteoblast-like cells seems to be a key element in VC pathogenesis, in the context of passive calcium and phosphate deposition due to abnormal bone metabolism and impaired renal excretion. The process may be favoured by the low levels of circulating and locally produced VC inhibitors. VC determines increased arterial stiffness, left ventricular hypertrophy, a decrease in coronary artery perfusion, myocardial ischaemia and increased cardiovascular morbidity and mortality. Although current therapeutic strategies focus on the correction of phosphate, calcium, parathyroid hormone or vitamin D, a better understanding of the mechanisms of abnormal tissue calcification may lead to development of new therapeutic agents, which could reduce VC and improve cardiovascular outcome in CKD patients. The present review summarizes the following aspects: (i) the pathophysiological mechanism responsible for VC and its promoters and inhibitors, (ii) the methods for detection of VC in patients with CKD, including evaluation of arterial stiffness, and (iii) the management of VC in CKD patients.
3
Ammirati, Adriano Luiz, Rosa Maria Affonso Moysés, and Maria Eugênia Canziani. "Vascular Calcification in Peritoneal Dialysis Patients." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 28, no. 2_suppl (March 2008): 20–25. http://dx.doi.org/10.1177/089686080802802s04.
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Vascular calcification (VC) is being recognized as a common complication at all stages of chronic kidney disease, particularly in patients on dialysis. Traditional and nontraditional cardiovascular risk factors both appear to be involved in the development of VC in this population. Although few studies focusing exclusively on peritoneal dialysis (PD) patients are available, some data support the view that VC constitutes an independent prognostic marker of morbidity and mortality in the PD population. In this review, we discuss the potential pathophysiologic pathways of VC in PD patients, and we examine the relevant clinical data.
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Lee, Sun Joo, In-Kyu Lee, and Jae-Han Jeon. "Vascular Calcification—New Insights into Its Mechanism." International Journal of Molecular Sciences 21, no. 8 (April 13, 2020): 2685. http://dx.doi.org/10.3390/ijms21082685.
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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.
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Phan, Olivier, and Nobuhiko Joki. "Vascular Calcification in Diabetic Kidney Disease." Kidney and Dialysis 2, no. 4 (December 1, 2022): 595–606. http://dx.doi.org/10.3390/kidneydial2040054.
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The pathogenesis of vascular calcification (VC) in diabetes mellitus (DM) has not been completely elucidated. VC often occur in patients with DM and chronic kidney disease (CKD). The incidence of VC in diabetic patients is more frequent than in nondiabetic patients, which is an important cause of cardiovascular (CV) morbidity and mortality. VC is a progressive transformation of the vascular wall; it results from an active and complex phenomenon affecting particularly the vascular smooth muscle cells (VSMCs). It leads to a change in the phenotype of the VSMCs towards an osteoblastic-like phenotype. DM is associated with specific risk factors in addition to hyperglycemia, such as increased oxidative stress, proinflammatory state, hypertension, and chronic kidney disease (CKD) promoting endothelial dysfunction. This article provides an overview and update of the pathophysiological data on the role of DM in VC progression.
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Lu, Kuo-Cheng, Chia-Chao Wu, Jen-Fen Yen, and Wen-Chih Liu. "Vascular Calcification and Renal Bone Disorders." Scientific World Journal 2014 (2014): 1–20. http://dx.doi.org/10.1155/2014/637065.
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At the early stage of chronic kidney disease (CKD), the systemic mineral metabolism and bone composition start to change. This alteration is known as chronic kidney disease-mineral bone disorder (CKD-MBD). It is well known that the bone turnover disorder is the most common complication of CKD-MBD. Besides, CKD patients usually suffer from vascular calcification (VC), which is highly associated with mortality. Many factors regulate the VC mechanism, which include imbalances in serum calcium and phosphate, systemic inflammation, RANK/RANKL/OPG triad, aldosterone, microRNAs, osteogenic transdifferentiation, and effects of vitamins. These factors have roles in both promoting and inhibiting VC. Patients with CKD usually have bone turnover problems. Patients with high bone turnover have increase of calcium and phosphate release from the bone. By contrast, when bone turnover is low, serum calcium and phosphate levels are frequently maintained at high levels because the reservoir functions of bone decrease. Both of these conditions will increase the possibility of VC. In addition, the calcified vessel may secrete FGF23 and Wnt inhibitors such as sclerostin, DKK-1, and secreted frizzled-related protein to prevent further VC. However, all of them may fight back the inhibition of bone formation resulting in fragile bone. There are several ways to treat VC depending on the bone turnover status of the individual. The main goals of therapy are to maintain normal bone turnover and protect against VC.
7
Siracusa, Chiara, Nicole Carabetta, Maria Benedetta Morano, Marzia Manica, Antonio Strangio, Jolanda Sabatino, Isabella Leo, et al. "Understanding Vascular Calcification in Chronic Kidney Disease: Pathogenesis and Therapeutic Implications." International Journal of Molecular Sciences 25, no. 23 (December 5, 2024): 13096. https://doi.org/10.3390/ijms252313096.
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Vascular calcification (VC) is a biological phenomenon characterized by an accumulation of calcium and phosphate deposits within the walls of blood vessels causing the loss of elasticity of the arterial walls. VC plays a crucial role in the incidence and progression of chronic kidney disease (CKD), leading to a significant increase in cardiovascular mortality in these patients. Different conditions such as age, sex, dyslipidemia, diabetes, and hypertension are the main risk factors in patients affected by chronic kidney disease. However, VC may occur earlier and faster in these patients if it is associated with new or non-traditional risk factors such as oxidative stress, anemia, and inflammation. In chronic kidney disease, several pathophysiological processes contribute to vascular calcifications, including osteochondrogenic differentiation of vascular cells, hyperphosphatemia and hypercalcemia, and the loss of specific vascular calcification inhibitors including pyrophosphate, fetuin-A, osteoprotegerin, and matrix GLA protein. In this review we discuss the main traditional and non-traditional risk factors that can promote VC in patients with kidney disease. In addition, we provide an overview of the main pathogenetic mechanisms responsible for VC that may be crucial to identify new prevention strategies and possible new therapeutic approaches to reduce cardiovascular risk in patients with kidney disease.
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Herrmann, Jaqueline, Milen Babic, Markus Tölle, Markus van der Giet, and Mirjam Schuchardt. "Research Models for Studying Vascular Calcification." International Journal of Molecular Sciences 21, no. 6 (March 23, 2020): 2204. http://dx.doi.org/10.3390/ijms21062204.
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Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are lacking. Due to the complex pathophysiology, various research models exist evaluating different aspects of VC. This review aims to give an overview of the cell and animal models used so far to study the molecular processes of VC. Here, in vitro cell culture models of different origins, ex vivo settings using aortic tissue and various in vivo disease-induced animal models are summarized. They reflect different aspects and depict the (patho)physiologic mechanisms within the VC process.
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Tsai, You-Tien, Hsiang-Yuan Yeh, Chia-Ter Chao, and Chih-Kang Chiang. "Superoxide Dismutase 2 (SOD2) in Vascular Calcification: A Focus on Vascular Smooth Muscle Cells, Calcification Pathogenesis, and Therapeutic Strategies." Oxidative Medicine and Cellular Longevity 2021 (February 24, 2021): 1–9. http://dx.doi.org/10.1155/2021/6675548.
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Vascular calcification (VC) describes the pathophysiological phenotype of calcium apatite deposition within the vascular wall, leading to vascular stiffening and the loss of compliance. VC is never benign; the presence and severity of VC correlate closely with the risk of myocardial events and cardiovascular mortality in multiple at-risk populations such as patients with diabetes and chronic kidney disease. Mitochondrial dysfunction involving each of vascular wall constituents (endothelia and vascular smooth muscle cells (VSMCs)) aggravates various vascular pathologies, including atherosclerosis and VC. However, few studies address the pathogenic role of mitochondrial dysfunction during the course of VC, and mitochondrial reactive oxygen species (ROS) seem to lie in the pathophysiologic epicenter. Superoxide dismutase 2 (SOD2), through its preferential localization to the mitochondria, stands at the forefront against mitochondrial ROS in VSMCs and thus potentially modifies the probability of VC initiation or progression. In this review, we will provide a literature-based summary regarding the relationship between SOD2 and VC in the context of VSMCs. Apart from the conventional wisdom of attenuating mitochondrial ROS, SOD2 has been found to affect mitophagy and the formation of the autophagosome, suppress JAK/STAT as well as PI3K/Akt signaling, and retard vascular senescence, all of which underlie the beneficial influences on VC exerted by SOD2. More importantly, we outline the therapeutic potential of a novel SOD2-targeted strategy for the treatment of VC, including an ever-expanding list of pharmaceuticals and natural compounds. It is expected that VSMC SOD2 will become an important druggable target for treating VC in the future.
10
Zhou, Zekun, Yi Li, Wei Jiang, and Zengli Wang. "Molecular Mechanism of Calycosin Inhibited Vascular Calcification." Nutrients 16, no. 1 (December 27, 2023): 99. http://dx.doi.org/10.3390/nu16010099.
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Vascular calcification (VC) is a pathological condition frequently observed in cardiovascular diseases. Primary factors contributing to VC are osteogenic differentiation of vascular smooth muscle and hydroxyapatite deposition. Targeted autophagy (a lysosome-mediated mechanism for degradation/recycling of unnecessary cellular components) is a useful approach for inhibiting VC and promoting vascular cell health. Calycosin has been shown to alleviate atherosclerosis by enhancing macrophage autophagy, but its therapeutic effect on VC has not been demonstrated. Using an in vitro model (rat thoracic aortic smooth muscle cell line A7r5), we demonstrated effective inhibition of VC using calycosin (the primary flavonoid component of astragalus), based on the enhancement of autophagic flux. Calycosin treatment activated AMPK/mTOR signaling to induce initiation of autophagy and restored mTORC1-dependent autophagosome–lysosome fusion in late-stage autophagy by promoting soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation, thereby preventing stoppage of autophagy in calcified cells. Calycosin substantially reduced degrees of both osteogenic differentiation and calcium deposition in our VC cell model by enhancing autophagy. The present findings clarify the mechanism whereby calycosin mitigates autophagy stoppage in calcified smooth muscle cells and provide a basis for effective VC treatment via autophagy enhancement.
11
Silva, Ana P., Carla S. B. Viegas, Filipa Mendes, Ana Macedo, Patrícia Guilherme, Nelson Tavares, Carolina Dias, et al. "Gla-Rich Protein (GRP) as an Early and Novel Marker of Vascular Calcification and Kidney Dysfunction in Diabetic Patients with CKD: A Pilot Cross-Sectional Study." Journal of Clinical Medicine 9, no. 3 (February 27, 2020): 635. http://dx.doi.org/10.3390/jcm9030635.
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Vascular calcification (VC) is one of the strongest predictors of cardiovascular risk in chronic kidney disease (CKD) patients. New diagnostic/prognostic tools are required for early detection of VC allowing interventional strategies. Gla-rich protein (GRP) is a cardiovascular calcification inhibitor, whose clinical utility is here highlighted. The present study explores, for the first time, correlations between levels of GRP in serum with CKD developmental stage, mineral metabolism markers, VC and pulse pressure (PP), in a cohort of 80 diabetic patients with mild to moderate CKD (stages 2–4). Spearman’s correlation analysis revealed a positive association of GRP serum levels with estimated glomerular filtration rate (eGFR) and α-Klotho, while a negative correlation with phosphate (P), fibroblast growth factor 23 (FGF-23), vascular calcification score (VCS), PP, calcium (x) phosphate (CaxP) and interleukin 6 (IL-6). Serum GRP levels were found to progressively decrease from stage 2 to stage 4 CKD. Multivariate analysis identified low levels of eGFR and GRP, and high levels of FGF-23 associated with both the VCS and PP. These results indicate an association between GRP, renal dysfunction and CKD-mineral and bone disorder. The relationship between low levels of GRP and vascular calcifications suggests a future, potential utility for GRP as an early marker of vascular damage in CKD.
12
Neto, Ricardo, Luciano Pereira, Juliana Magalhães, Janete Quelhas-Santos, and João Frazão. "Low bone turnover is associated with plain X-ray vascular calcification in predialysis patients." PLOS ONE 16, no. 10 (October 13, 2021): e0258284. http://dx.doi.org/10.1371/journal.pone.0258284.
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Background Vascular calcification (VC) is a common finding in chronic kidney disease (CKD) patients and predicts subsequent cardiovascular morbidity and mortality in this population. Vascular calcification is linked to disordered mineral metabolism and has been associated with bone histomorphometry changes in CKD. However, data on predialysis patients is scarce. Methods A cross-sectional study was conducted on a cohort of 56 CKD patients not yet on dialysis, who underwent a transiliac bone biopsy for histomorphometric evaluation after double tetracycline labeling. Patients had no previous exposure to calcium salts, vitamin D agents, steroids or bisphosphonates. Vascular calcification was assessed at the time of biopsy, using Kauppila (plain X-ray of the lateral lumbar spine) and Adragão (plain X-ray of the pelvis and hands) scores. Results Vascular calcification was seen in two-thirds of the cohort. Subjects with VC were more likely to be male and have diabetes, and had significantly higher sclerostin and osteoprotegerin circulating levels than those without VC. The histomorphometric analysis showed that bone formation rate was significantly lower in VC compared to non-VC patients. In the multivariable logistic regression analysis, bone formation rate was independently associated with the presence of VC. Conclusions Vascular calcification is highly prevalent in predialysis patients, especially in those with diabetes. The independent association between bone formation rate and VC provides evidence of an important interaction between bone and vessel in CKD. Our results suggest that low bone turnover is a non-traditional risk factor for cardiovascular disease in predialysis patients.
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Lee, Chien-Te, Sarah Chua, Chung-Yao Hsu, Yu-Che Tsai, Hwee-Yeong Ng, Chien-Chun Kuo, Chien-Hsing Wu, Te-Chun Chen, Terry Ting-Yu Chiu, and Yueh-Ting Lee. "Biomarkers Associated with Vascular and Valvular Calcification in Chronic Hemodialysis Patients." Disease Markers 34, no. 4 (2013): 229–35. http://dx.doi.org/10.1155/2013/846059.
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Background: Cardiovascular calcification, including arterial intimal and medial calcification (AIC and AMC) and valvular calcification (VC) are important predictors of outcome in chronic dialysis patients. We aimed to compare their prevalence and analyze respective risk factors in hemodialysis (HD) patients.Methods: A total of 81 HD patients were enrolled. Vascular calcification was assessed by plain film radiography of the pelvis and VC was diagnosed by echocardiography. Demographic data was reviewed and serum levels of calcification-relevant biomarkers were determined. Patients with and without calcification were then compared.Results: The prevalence study indicated that 36 patients had AIC (44.4%), 17 had AMC (21%) and 60 (74.1%) had VC. Patients with vascular calcification were older, and had a higher prevalence of diabetes. Their IL-6, osteoprotegerin, and uric acid levels were higher. Serum fetuin-A was lower in patients with VC. Logistic regression analysis revealed age, uric acid and diabetes to be independently associated with AIC; uric acid, diabetes and osteoprotegerin with AMC. Fetuin-A was the sole associate of VC.Conclusions: It is concluded that the prevalence of cardiovascular calcification in chronic HD patients was high with cardiac valve involvement more frequent. Factors associated with different type of calcification were not identical. Changes in biomarkers may represent clinical clues for assessment of cardiovascular calcification in HD patients.
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Silaghi, Ciprian N., Tamás Ilyés, Adriana J. Van Ballegooijen, and Alexandra M. Crăciun. "Calciprotein Particles and Serum Calcification Propensity: Hallmarks of Vascular Calcifications in Patients with Chronic Kidney Disease." Journal of Clinical Medicine 9, no. 5 (April 29, 2020): 1287. http://dx.doi.org/10.3390/jcm9051287.
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Cardiovascular complications are one of the leading causes of mortality worldwide and are strongly associated with atherosclerosis and vascular calcification (VC). Patients with chronic kidney disease (CKD) have a higher prevalence of VC as renal function declines, which will result in increased mortality. Serum calciprotein particles (CPPs) are colloidal nanoparticles that have a prominent role in the initiation and progression of VC. The T50 test is a novel test that measures the conversion of primary to secondary calciprotein particles indicating the tendency of serum to calcify. Therefore, we accomplished a comprehensive review as the first integrated approach to clarify fundamental aspects that influence serum CPP levels and T50, and to explore the effects of CPP and calcification propensity on various chronic disease outcomes. In addition, new topics were raised regarding possible clinical uses of T50 in the assessment of VC, particularly in patients with CKD, including possible opportunities in VC management. The relationships between serum calcification propensity and cardiovascular and all-cause mortality were also addressed. The review is the outcome of a comprehensive search on available literature and could open new directions to control VC.
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Cozzolino, Mario, Paola Ciceri, Andrea Galassi, Michela Mangano, Stefano Carugo, Irene Capelli, and Giuseppe Cianciolo. "The Key Role of Phosphate on Vascular Calcification." Toxins 11, no. 4 (April 9, 2019): 213. http://dx.doi.org/10.3390/toxins11040213.
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Vascular calcification (VC) is common in dialysis and non-dialysis chronic kidney disease (CKD) patients, even in the early stage of the disease. For this reason, it can be considered a CKD hallmark. VC contributes to cardiovascular disease (CVD) and increased mortality among CKD patients, although it has not been proven. There are more than one type of VC and every form represents a marker of systemic vascular disease and is associated with a higher prevalence of CVD in CKD patients, as shown by several clinical studies. Major risk factors for VC in CKD include: Increasing age, dialysis vintage, hyperphosphatemia (particularly in the setting of intermittent or persistent hypercalcemia), and a positive net calcium and phosphate balance. Excessive oral calcium intake, including calcium-containing phosphate binders, increases the risk for VC. Moreover, it has been demonstrated that there is less VC progression with non-calcium-containing phosphate binders. Unfortunately, until now, a specific therapy to prevent progression or to facilitate regression of VC has been found, beyond careful attention to calcium and phosphate balance.
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Akers, Emma J., Stephen J. Nicholls, and Belinda A. Di Bartolo. "Plaque Calcification." Arteriosclerosis, Thrombosis, and Vascular Biology 39, no. 10 (October 2019): 1902–10. http://dx.doi.org/10.1161/atvbaha.119.311574.
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Vascular calcification (VC) is strongly associated with all-cause mortality and is an independent predictor of cardiovascular events. Resulting from its complex, multifaceted nature, targeted treatments for VC have not yet been developed. Lipoproteins are well characterized in the pathogenesis of atherosclerotic plaques, leading to the development of plaque regressing therapeutics. Although their roles in plaque progression are well documented, their roles in VC, and calcification of a plaque, are not well understood. In this review, early in vitro data and clinical correlations suggest an inhibitory role for HDL (high-density lipoproteins) in VC, a stimulatory role for LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) and a potentially causal role for Lp(a) (lipoprotein [a]). Additionally, after treatment with a statin or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, plaque calcification is observed to increase. With the notion that differing morphologies of plaque calcification associate with either a more stable or unstable plaque phenotype, uncovering the mechanisms of lipoprotein-artery wall interactions could produce targeted therapeutic options for VC.
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Wang, Pengbo, Naijin Zhang, Boquan Wu, Shaojun Wu, Ying Zhang, and Yingxian Sun. "The role of mitochondria in vascular calcification." Journal of Translational Internal Medicine 8, no. 2 (June 30, 2020): 80–90. http://dx.doi.org/10.2478/jtim-2020-0013.
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AbstractVascular calcification (VC) was defined as the ectopic deposition of calcium–phosphorus complexes on the blood vessel walls. It was a process involving multiple factors and mechanisms, covering the phenotype transition of vascular smooth muscle cells (VSMCs) and release of microvesicles. It was a common end-stage alteration of chronic diseases such as cardiovascular disease and chronic kidney disease. Increasing evidence indicates that mitochondria were involved in the development of VC. Mitochondria provided energy to cells, maintained the stability of cell functions, and participated in a variety of biological behavior. Oxidative stress, autophagy, apoptosis, and mitochondrial DNA (mtDNA) damage could affect the development of VSMCs calcification by alteration of mitochondrial function. This article reviewed the mechanism of calcification and the role of mitochondria in VC, aiming to raise a novel insight into drug development and clinical treatment.
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Abbasian, Nima. "Vascular Calcification Mechanisms: Updates and Renewed Insight into Signaling Pathways Involved in High Phosphate-Mediated Vascular Smooth Muscle Cell Calcification." Biomedicines 9, no. 7 (July 12, 2021): 804. http://dx.doi.org/10.3390/biomedicines9070804.
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Vascular calcification (VC) is associated with aging, cardiovascular and renal diseases and results in poor morbidity and increased mortality. VC occurs in patients with chronic kidney disease (CKD), a condition that is associated with high serum phosphate (Pi) and severe cardiovascular consequences. High serum Pi level is related to some pathologies which affect the behaviour of vascular cells, including platelets, endothelial cells (ECs) and smooth muscle cells (SMCs), and plays a central role in promoting VC. VC is a complex, active and cell-mediated process involving the transdifferentiation of vascular SMCs to a bone-like phenotype, systemic inflammation, decreased anti-calcific events (loss of calcification inhibitors), loss in SMC lineage markers and enhanced pro-calcific microRNAs (miRs), an increased intracellular calcium level, apoptosis, aberrant DNA damage response (DDR) and senescence of vascular SMCs. This review gives a brief overview of the current knowledge of VC mechanisms with a particular focus on Pi-induced changes in the vascular wall important in promoting calcification. In addition to reviewing the main findings, this review also sheds light on directions for future research in this area and discusses emerging pathways such as Pi-regulated intracellular calcium signaling, epigenetics, oxidative DNA damage and senescence-mediated mechanisms that may play critical, yet to be explored, regulatory and druggable roles in limiting VC.
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Ureña-Torres, Pablo, Luis D’Marco, Paolo Raggi, Xavier García–Moll, Vincent Brandenburg, Sandro Mazzaferro, Ari Lieber, Lluis Guirado, and Jordi Bover. "Valvular heart disease and calcification in CKD: more common than appreciated." Nephrology Dialysis Transplantation 35, no. 12 (July 21, 2019): 2046–53. http://dx.doi.org/10.1093/ndt/gfz133.
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Abstract Ischaemic heart disease, sudden cardiac death and arrhythmias, heart failure, stroke and peripheral arterial disease make up >50% of the causes of death in advanced chronic kidney disease (CKD). Calcification of the vascular tree and heart valves is partially related to these complications and has received growing attention in the literature. However, the main focus of research has been on the pathophysiology and consequences of vascular calcification, with less attention being paid to valvular calcification (VC) and its impact on the survival of CKD patients. Although VC has long been seen as an age-related degenerative disorder with minimal functional impact, several studies proved that it carries an increased risk of death and clinical consequences different from those of vascular calcification. In dialysis patients, the annual incidence of aortic valve calcification is nearly 3.3% and the reported prevalence of aortic and mitral VC varies between 25% and 59%. Moreover, calcification of both valves occurs 10–20 years earlier in CKD patients compared with the general population. Therefore, the purpose of this review is to summarize the current knowledge on the pathophysiology and relevance of VC in CKD patients, and to highlight specific clinical consequences and potential therapeutic implications.
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Chao, Chia-Ter, Hsiang-Yuan Yeh, You-Tien Tsai, Tzu-Hang Yuan, Min-Tser Liao, Jenq-Wen Huang, and Huei-Wen Chen. "Astaxanthin Counteracts Vascular Calcification In Vitro Through an Early Up-Regulation of SOD2 Based on a Transcriptomic Approach." International Journal of Molecular Sciences 21, no. 22 (November 12, 2020): 8530. http://dx.doi.org/10.3390/ijms21228530.
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Vascular calcification (VC) is a critical contributor to the rising cardiovascular risk among at-risk populations such as those with diabetes or renal failure. The pathogenesis of VC involves an uprising of oxidative stress, for which antioxidants can be theoretically effective. However, astaxanthin, a potent antioxidant, has not been tested before for the purpose of managing VC. To answer this question, we tested the efficacy of astaxanthin against VC using the high phosphate (HP)-induced vascular smooth muscle cell (VSMC) calcification model. RNAs from treated groups underwent Affymetrix microarray screening, with intra-group consistency and inter-group differential expressions identified. Candidate hub genes were selected, followed by validation in experimental models and functional characterization. We showed that HP induced progressive calcification among treated VSMCs, while astaxanthin dose-responsively and time-dependently ameliorated calcification severities. Transcriptomic profiling revealed that 3491 genes exhibited significant early changes during VC progression, among which 26 potential hub genes were selected based on closeness ranking and biologic plausibility. SOD2 was validated in the VSMC model, shown to drive the deactivation of cellular senescence and enhance antioxidative defenses. Astaxanthin did not alter intracellular reactive oxygen species (ROS) levels without HP, but significantly lowered ROS production in HP-treated VSMCs. SOD2 knockdown prominently abolished the anti-calcification effect of astaxanthin on HP-treated VSMCs, lending support to our findings. In conclusion, we demonstrated for the first time that astaxanthin could be a potential candidate treatment for VC, through inducing the up-regulation of SOD2 early during calcification progression and potentially suppressing vascular senescence.
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Moldovan, Diana, Crina Rusu, Alina Potra, Dacian Tirinescu, Maria Ticala, and Ina Kacso. "Food to Prevent Vascular Calcification in Chronic Kidney Disease." Nutrients 16, no. 5 (February 23, 2024): 617. http://dx.doi.org/10.3390/nu16050617.
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Vascular calcification (VC) is a consequence of chronic kidney disease (CKD) which is of paramount importance regarding the survival of CKD patients. VC is far from being controlled with actual medication; as a result, in recent years, diet modulation has become more compelling. The concept of medical nutritional therapy points out the idea that food may prevent or treat diseases. The aim of this review was to evaluate the influence of food habits and nutritional intervention in the occurrence and progression of VC in CKD. Evidence reports the harmfulness of ultra-processed food, food additives, and animal-based proteins due to the increased intake of high absorbable phosphorus, the scarcity of fibers, and the increased production of uremic toxins. Available data are more supportive of a plant-dominant diet, especially for the impact on gut microbiota composition, which varies significantly depending on VC presence. Magnesium has been shown to prevent VC but only in experimental and small clinical studies. Vitamin K has drawn considerable attention due to its activation of VC inhibitors. There are positive studies; unfortunately, recent trials failed to prove its efficacy in preventing VC. Future research is needed and should aim to transform food into a medical intervention to eliminate VC danger in CKD.
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Lu, Chien-Lin, Min-Tser Liao, Yi-Chou Hou, Yu-Wei Fang, Cai-Mei Zheng, Wen-Chih Liu, Chia-Ter Chao, Kuo-Cheng Lu, and Yee-Yung Ng. "Sirtuin-1 and Its Relevance in Vascular Calcification." International Journal of Molecular Sciences 21, no. 5 (February 26, 2020): 1593. http://dx.doi.org/10.3390/ijms21051593.
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Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.
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Izzo, Carmine, Carmine Secondulfo, Giancarlo Bilancio, Valeria Visco, Nicola Virtuoso, Serena Migliarino, Michele Ciccarelli, et al. "Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview." Life 14, no. 3 (March 21, 2024): 418. http://dx.doi.org/10.3390/life14030418.
Full textAbstract:
Chronic kidney disease (CKD) is a global health issue with a rising prevalence, affecting 697.5 million people worldwide. It imposes a substantial burden, contributing to 35.8 million disability-adjusted life years (DALYs) and 1.2 million deaths in 2017. The mortality rate for CKD has increased by 41.5% between 1990 and 2017, positioning it as a significant cause of global mortality. CKD is associated with diverse health complications, impacting cardiovascular, neurological, nutritional, and endocrine aspects. One prominent complication is CKD–mineral and bone disorder (MBD), a complex condition involving dysregulation of bone turnover, mineralization, and strength, accompanied by soft tissue and vascular calcification. Alterations in mineral metabolism, including calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and Klotho, play pivotal roles in CKD-MBD. These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy (ROD). Vascular calcification (VC) is a key component of CKD-MBD, accelerated by CKD. The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). VC is closely linked to cardiovascular events and mortality, emphasizing its prognostic significance. Various serum markers and imaging techniques, including lateral plain X-ray, Kauppila Score, Adragao Score, and pulse wave velocity, aid in VC detection. Additionally, pQCT provides valuable information on arterial calcifications, offering an advantage over traditional scoring systems. CKD poses a substantial global health burden, and its complications, including CKD-MBD and VC, significantly contribute to morbidity and mortality. Understanding the intricate relationships between mineral metabolism, bone disorders, and vascular calcification is crucial for effective diagnosis and therapeutic interventions.
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Ceccherini, Elisa, Elisa Persiani, Manuela Cabiati, Letizia Guiducci, Silvia Del Ry, Ilaria Gisone, Alessandra Falleni, Antonella Cecchettini, and Federico Vozzi. "A Dynamic Cellular Model as an Emerging Platform to Reproduce the Complexity of Human Vascular Calcification In Vitro." International Journal of Molecular Sciences 25, no. 13 (July 6, 2024): 7427. http://dx.doi.org/10.3390/ijms25137427.
Full textAbstract:
Vascular calcification (VC) is a cardiovascular disease characterized by calcium salt deposition in vascular smooth muscle cells (VSMCs). Standard in vitro models used in VC investigations are based on VSMC monocultures under static conditions. Although these platforms are easy to use, the absence of interactions between different cell types and dynamic conditions makes these models insufficient to study key aspects of vascular pathophysiology. The present study aimed to develop a dynamic endothelial cell–VSMC co-culture that better mimics the in vivo vascular microenvironment. A double-flow bioreactor supported cellular interactions and reproduced the blood flow dynamic. VSMC calcification was stimulated with a DMEM high glucose calcification medium supplemented with 1.9 mM NaH2PO4/Na2HPO4 (1:1) for 7 days. Calcification, cell viability, inflammatory mediators, and molecular markers (SIRT-1, TGFβ1) related to VSMC differentiation were evaluated. Our dynamic model was able to reproduce VSMC calcification and inflammation and evidenced differences in the modulation of effectors involved in the VSMC calcified phenotype compared with standard monocultures, highlighting the importance of the microenvironment in controlling cell behavior. Hence, our platform represents an advanced system to investigate the pathophysiologic mechanisms underlying VC, providing information not available with the standard cell monoculture.
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Zhang, Zhenghong, Defan Wang, Renfeng Xu, Xiang Li, Zhengchao Wang, and Yang Zhang. "The Physiological Functions and Therapeutic Potential of Hypoxia-Inducible Factor-1α in Vascular Calcification." Biomolecules 14, no. 12 (December 12, 2024): 1592. https://doi.org/10.3390/biom14121592.
Full textAbstract:
HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates gene expressions related to calcification. Additionally, HIF-1α modulates the metabolic state of VSMCs by regulating the pathways that govern the switch between glycolysis and oxidative phosphorylation, thereby further advancing the calcification process. The interaction between HIF-1α and other signaling pathways, such as nuclear factor-κB, Notch, and Wnt/β-catenin, creates a complex regulatory network that serves as a critical driving force in VC. Therefore, a deeper understanding of the role and regulatory mechanism of the HIF-1α signaling during the development and progression of VC is of great significance, as it is not only a key molecular marker for understanding the pathological mechanisms of VC but also represents a promising target for future anti-calcification therapies.
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Pavlic, Angelina, Nasim Bahram Sangani, Johanna Kerins, Gerry Nicolaes, Leon Schurgers, and Chris Reutelingsperger. "Vascular Smooth Muscle Cell Neutral Sphingomyelinase 2 in the Release of Exosomes and Vascular Calcification." International Journal of Molecular Sciences 23, no. 16 (August 16, 2022): 9178. http://dx.doi.org/10.3390/ijms23169178.
Full textAbstract:
Vascular calcification (VC) is the pathological precipitation of calcium salts in the walls of blood vessels. It is a risk factor for cardiovascular events and their associated mortality. VC can be observed in a variety of cardiovascular diseases and is most prominent in diseases that are associated with dysregulated mineral homeostasis such as in chronic kidney disease. Local factors and mechanisms underlying VC are still incompletely understood, but it is appreciated that VC is a multifactorial process in which vascular smooth muscle cells (VSMCs) play an important role. VSMCs participate in VC by releasing extracellular vesicles (EVs), the extent, composition, and propensity to calcify of which depend on VSMC phenotype and microenvironment. Currently, no targeted therapy is available to treat VC. In-depth knowledge of molecular players of EV release and the understanding of their mechanisms constitute a vital foundation for the design of pharmacological treatments to combat VC effectively. This review highlights our current knowledge of VSMCs in VC and focuses on the biogenesis of exosomes and the role of the neutral Sphingomyelinase 2 (nSMase2).
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Yang, Yanli, Na Lin, Yuankai Xu, Zheli Niu, Fulei Meng, Kaidi Zhang, Yuhuan Wang, Lin Ruan, and Lihong Zhang. "Calcification detection on upper extremity arteries: a comparison of ultrasonic and X-ray methods." PeerJ 11 (August 23, 2023): e15855. http://dx.doi.org/10.7717/peerj.15855.
Full textAbstract:
Background Vascular calcification (VC) has been observed in patients with hemodialysis, whereas few studies have investigated calcification in the upper extremity vasculature. Both ultrasound and X-ray are used to investigate the calcification of arteries in patients. However, there is a lack of data on the consistency between these two methods. The aim of this study was to investigate the occurrence of VC in the radial and ulnar arteries of hemodialysis patients and investigate the detection consistency in VC between ultrasound and X-ray. Methods Ultrasound and X-ray examinations were performed in the radial and ulnar arteries of both the left and right upper extremities of 40 patients on hemodialysis. The calcification status of arteries was evaluated by the calcification index from ultrasound and X-ray respectively. Clinical variables of patients were collected from all the involved patients. Results Of the 40 patients, VC was detected in 31 patients by ultrasound, while X-ray detected VC in 22 patients. Compared to ultrasound assessment, X-ray assessment was 73.21% sensitive but only 66.35% specific with a positive predictive value of 53.95% for detecting calcifications in the radial or ulnar artery. The level of agreement between ultrasound and X-ray results was fair. In addition, our data showed that more ulnar arteries had VCs than the corresponding radial arteries. Conclusion Ultrasound is more sensitive in detecting the presence of calcified atherosclerotic lesions. Ultrasound and X-ray exhibited fair consistency. Ultrasound screening for upper extremity radial and ulnar arteries in hemodialysis patients may deserve attention to explore its clinical significance.
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Hou, Yi-Chou, Chien-Lin Lu, Tzu-Hang Yuan, Min-Tser Liao, Chia-Ter Chao, and Kuo-Cheng Lu. "The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective." International Journal of Molecular Sciences 21, no. 3 (February 1, 2020): 980. http://dx.doi.org/10.3390/ijms21030980.
Full textAbstract:
Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk.
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Carrillo-López, Natalia, Sara Panizo, Beatriz Martín-Carro, Juan Carlos Mayo Barrallo, Pablo Román-García, Raúl García-Castro, Jesús María Fernández-Gómez, et al. "Redox Metabolism and Vascular Calcification in Chronic Kidney Disease." Biomolecules 13, no. 9 (September 20, 2023): 1419. http://dx.doi.org/10.3390/biom13091419.
Full textAbstract:
Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, the main scavenger of H2O2, remains unclear. In the present study, epigastric arteries of kidney transplant recipients, a rat model of VC, and an in vitro model of VC exhibiting catalase (Cts) overexpression were analysed. Pericalcified areas of human epigastric arteries had increased levels of catalase and cytoplasmic, rather than nuclear runt-related transcription factor 2 (RUNX2). In the rat model, advanced aortic VC concurred with lower levels of the H2O2-scavenger glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in total levels of RUNX2. However, Cts VMSCs also exhibited a lower percentage of the nucleus stained for RUNX2 in response to calcifying media. In this early model of VC, we did not observe a dysregulation of the mitochondrial redox state; instead, an increase in the general redox state was observed in the cytoplasm. These results highlight the complex role of antioxidant enzymes as catalase by regulation of RUNX2 subcellular location delaying the onset of VC.
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Yaker, Linda, Saïd Kamel, Jérôme Ausseil, and Agnès Boullier. "Effects of Chronic Kidney Disease and Uremic Toxins on Extracellular Vesicle Biology." Toxins 12, no. 12 (December 21, 2020): 811. http://dx.doi.org/10.3390/toxins12120811.
Full textAbstract:
Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate, especially in patients with diabetes, atherosclerosis or chronic kidney disease (CKD). In CKD patients, VC is associated with the accumulation of uremic toxins, such as indoxyl sulphate or inorganic phosphate, which can have a major impact in vascular remodeling. During VC, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch and secrete extracellular vesicles (EVs) that are heterogeneous in terms of their origin and composition. Under physiological conditions, EVs are involved in cell-cell communication and the maintenance of cellular homeostasis. They contain high levels of calcification inhibitors, such as fetuin-A and matrix Gla protein. Under pathological conditions (and particularly in the presence of uremic toxins), the secreted EVs acquire a pro-calcifying profile and thereby act as nucleating foci for the crystallization of hydroxyapatite and the propagation of calcification. Here, we review the most recent findings on the EVs’ pathophysiological role in VC, the impact of uremic toxins on EV biogenesis and functions, the use of EVs as diagnostic biomarkers and the EVs’ therapeutic potential in CKD.
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Ciceri, Paola, Andrea Galassi, Carlo Alfieri, Piergiorgio Messa, and Mario Cozzolino. "Uremic Patients with Increased Vascular Calcification Score Have Serum with High Calcific Potential: Role of Vascular Smooth Muscle Cell Osteoblastic Differentiation and Apoptosis." Blood Purification 48, no. 2 (2019): 142–49. http://dx.doi.org/10.1159/000497229.
Full textAbstract:
Background/Aims: Uremic patients experience premature vascular ageing that causes cardiovascular morbidity. In this study, we investigated the relationship between uremic serum calcific potential induced by high phosphate (Pi) and vascular calcification score (VCS). Methods: Vascular smooth muscle cells (VSMCs) were cultured with 3.5 mM Na3PO4 (Pi) with 10% uremic serum and calcium deposition, markers of osteoblastic transformation, and apoptosis were evaluated. Results: Culture with uremic serum and high-Pi significantly induced calcification (0.21 ± 0.03 vs. 8.05 ± 0.6; ctr vs. Pi; OD/mg protein; p < 0.01). We next stratified patients with respect of the degree of VCS in 2 groups: absence of vascular calcification (VC) “no VC group” and presence of VC “VC group”. We found that there was a significant correlation between VCS and uremic serum calcific potential induced by high Pi in vitro (p < 0.01). Interestingly, uremic sera of the “VC group” were more effective than sera from the “no VC group”, in downregulating α-actin and SM22α, after treatment with high-Pi (41.3 ± 4.7 vs. 23.3 ± 2.9 and 25.6 ± 6.8 vs. 8.14 ± 2.3; VC vs. no VC group, α-actin and SM22α respectively; Δ intensity area; p < 0.01). Similarly, sera from “VC group” were more effective than sera from “no VC group” in adjuvanting the high-Pi effect of increasing osteoblastic markers, such as bone morphogenic protein 2 (BMP2), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2; 39.1 ± 11.3 vs. 5.0 ± 2.6 BMP2; 12.2 ± 4.2 vs. 1.7 ± 0.3 OC; 2.9 ± 0.4 vs. 1.2 ± 0.2 RUNX2; VC vs. no VC group respectively; p < 0.05). We found a similar pattern with significantly higher apoptosis and necrosis induction by sera from the “VC group” compared to the “no VC group” (2.05 ± 0.33 vs. 1.29 ± 0.13 and 54.1 ± 19.5 vs. 27.4 ± 10.6; Pi; VC group vs. no VC group; enrichment factor of apoptotic or necrotic fragments, respectively; p < 0.05). Conclusions: We conclude that VCS of end-stage renal disease patients significantly correlates with serum-calcific potential induced by high Pi. In addition, uremic patients with higher VCS have sera with a higher potential to induce VSMC osteoblastic trans-differentiation, apoptosis, and necrosis.
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Soriano, Sagrario, Andrés Carmona, Francisco Triviño, Mariano Rodriguez, Marina Alvarez-Benito, Alejandro Martín-Malo, Maria-Antonia Alvarez-Lara, Rafael Ramírez, Pedro Aljama, and Julia Carracedo. "Endothelial damage and vascular calcification in patients with chronic kidney disease." American Journal of Physiology-Renal Physiology 307, no. 11 (December 1, 2014): F1302—F1311. http://dx.doi.org/10.1152/ajprenal.00114.2014.
Full textAbstract:
Vascular calcification (VC) is a frequent complication of chronic kidney disease (CKD) and is a predictor of cardiovascular morbidity and mortality. In the present study, we investigated the potential involvement of endothelial microparticles (MPs) and endothelial progenitor cells (EPCs) in the generation of VC in CKD patients. The number of circulating EMPs is greater in patients with VC than without VC (307 ± 167 vs. 99 ± 75 EMPs/μl, P < 0.001). The percentage of EPCs is significantly lower in patient with VC than in patients without VC (0.14 ± 0.11% vs. 0.25 ± 0.18%, P = 0.002). The number of EPCs expressing osteocalcin (OCN) was higher in VC patients (349 ± 63 cells/100,000) than in non-VC patients (139 ± 75 cells/100,000, P < 0.01). In vitro, MPs obtained from CKD patients were able to induce OCN expression in EPCs from healthy donors; the increase in OCN expression was more accentuated if MPs were obtained from CKD patients with VC. MPs from CKD patients also induced OCN expression in vascular smooth muscle cells and fibroblasts. In CKD patients, the rise in endothelial MPs associated with a decrease in the number of EPCs, suggesting an imbalance in the processes of endothelial damage and repair in CKD patients, mainly those with VC. Our results suggest that EPCs, through OCN expression, may directly participate in the process of VC.
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Liu, Shi-Meng, Ya-Rong Zhang, Yao Chen, Deng-Ren Ji, Jie Zhao, Su Fu, Mo-Zhi Jia, et al. "Intermedin Alleviates Vascular Calcification in CKD through Sirtuin 3-Mediated Inhibition of Mitochondrial Oxidative Stress." Pharmaceuticals 15, no. 10 (October 2, 2022): 1224. http://dx.doi.org/10.3390/ph15101224.
Full textAbstract:
Vascular calcification (VC) is a common pathophysiological process of chronic kidney disease (CKD). Sirtuin 3 (Sirt3), a major NAD+-dependent protein deacetylase predominantly in mitochondria, is involved in the pathogenesis of VC. We previously reported that intermedin (IMD) could protect against VC. In this study, we investigated whether IMD attenuates VC by Sirt3-mediated inhibition of mitochondrial oxidative stress. A rat VC with CKD model was induced by the 5/6 nephrectomy plus vitamin D3. Vascular smooth muscle cell (VSMC) calcification was induced by CaCl2 and β-glycerophosphate. IMD1-53 treatment attenuated VC in vitro and in vivo, rescued the depressed mitochondrial membrane potential (MMP) level and decreased mitochondrial ROS levels in calcified VSMCs. IMD1-53 treatment recovered the reduced protein level of Sirt3 in calcified rat aortas and VSMCs. Inhibition of VSMC calcification by IMD1-53 disappeared when the cells were Sirt3 absent or pretreated with the Sirt3 inhibitor 3-TYP. Furthermore, 3-TYP pretreatment blocked IMD1-53-mediated restoration of the MMP level and inhibition of mitochondrial oxidative stress in calcified VSMCs. The attenuation of VSMC calcification by IMD1-53 through upregulation of Sirt3 might be achieved through activation of the IMD receptor and post-receptor signaling pathway AMPK, as indicated by pretreatment with an IMD receptor antagonist or AMPK inhibitor blocking the inhibition of VSMC calcification and upregulation of Sirt3 by IMD1-53. AMPK inhibitor treatment reversed the effects of IMD1-53 on restoring the MMP level and inhibiting mitochondrial oxidative stress in calcified VSMCs. In conclusion, IMD attenuates VC by improving mitochondrial function and inhibiting mitochondrial oxidative stress through upregulating Sirt3.
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Viegas, Carla, Joana Carreira, Teresa M. Maia, Anjos L. Macedo, António P. Matos, José Neves, and Dina Simes. "Gla Rich Protein (GRP) Mediates Vascular Smooth Muscle Cell (VSMC) Osteogenic Differentiation, Extracellular Vesicle (EV) Calcification Propensity, and Immunomodulatory Properties." International Journal of Molecular Sciences 25, no. 22 (November 19, 2024): 12406. http://dx.doi.org/10.3390/ijms252212406.
Full textAbstract:
Vascular calcification (VC) is a complex process involving vascular smooth muscle cell (VSMC) osteogenic differentiation, inflammation, and extracellular vesicle (EV) calcification and communication networks. Gla rich protein (GRP) is a calcification inhibitor involved in most of these processes. However, the molecular mechanism of GRP in VC and the specific characteristics, cargo, and functionality of calcifying EVs require further elucidation. Here, we use a combination of human ex vivo aortic fragments and primary vascular smooth muscle cell (VSMC) models to obtain new information on GRP function in VC and EVs released by VSMCs. We demonstrate that GRP inhibits VSMC osteogenic differentiation through downregulation of bone-related proteins and upregulation of mineralization inhibitors, with decreased mineral crystallinity in EVs deposited into the tissue extracellular matrix (ECM). EVs isolated by ultracentrifugation at 30K and 100K from the cell media (CM) and deposited in the ECM from control (CTR) and mineralizing (MM) VSMCs were biochemically, physically, and proteomically characterized. Four different EV populations were identified with shared markers commonly present in all EVs but with unique protein cargo and specific molecular profiles. Comparative proteomics identified several regulated proteins specifically loaded into MM EV populations associated with multiple processes involved in VC. Functional analysis demonstrated that 30K and 100K ECM-MM EVs with higher calcium and lower GRP levels induced macrophage inflammation. Our findings reinforce the functional relevance of GRP in multiple VC processes and suggest that ECM EVs released under calcification stress function as a new signaling axis on the calcification–inflammation cycle.
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Marreiros, Catarina, Carla Viegas, and Dina Simes. "Targeting a Silent Disease: Vascular Calcification in Chronic Kidney Disease." International Journal of Molecular Sciences 23, no. 24 (December 17, 2022): 16114. http://dx.doi.org/10.3390/ijms232416114.
Full textAbstract:
Chronic kidney disease (CKD) patients have a higher risk of developing early cardiovascular disease (CVD). Although vascular calcification (VC) is one of the strongest predictors of CVD risk, its diagnosis among the CKD population remains a serious clinical challenge. This is mainly due to the complexity of VC, which results from various interconnected pathological mechanisms occurring at early stages and at multiples sites, affecting the medial and intimal layers of the vascular tree. Here, we review the most used and recently developed imaging techniques, here referred to as imaging biomarkers, for VC detection and monitoring, while discussing their strengths and limitations considering the specificities of VC in a CKD context. Although imaging biomarkers have a crucial role in the diagnosis of VC, with important insights into CVD risk, circulating biomarkers represent an added value by reflecting the molecular dynamics and mechanisms involved in VC pathophysiological pathways, opening new avenues into the early detection and targeted interventions. We propose that a combined strategy using imaging and circulating biomarkers with a role in multiple VC molecular mechanisms, such as Fetuin-A, Matrix Gla protein, Gla-rich protein and calciprotein particles, should represent high prognostic value for management of CVD risk in the CKD population.
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Galunska, Bistra, Yoto Yotov, Miglena Nikolova, and Atanas Angelov. "Extrahepatic Vitamin K-Dependent Gla-Proteins–Potential Cardiometabolic Biomarkers." International Journal of Molecular Sciences 25, no. 6 (March 20, 2024): 3517. http://dx.doi.org/10.3390/ijms25063517.
Full textAbstract:
One mechanism to regulate pathological vascular calcification (VC) is its active inhibition. Loss or inactivation of endogenic inhibitors is a major inductor of VC. Such inhibitors are proteins rich in gamma-glutamyl residues (Gla-proteins), whose function strongly depends on vitamin K. The current narrative review is focused on discussing the role of extrahepatic vitamin K-dependent Gla-proteins (osteocalcin, OC; matrix Gla-protein, MGP; Gla-rich protein, GRP) in cardio-vascular pathology. Gla-proteins possess several functionally active forms whose role in the pathogenesis of VC is still unclear. It is assumed that low circulating non-phosphorylated MGP is an indicator of active calcification and could be a novel biomarker of prevalent VC. High circulating completely inactive MGP is proposed as a novel risk factor for cardio-vascular events, disease progression, mortality, and vitamin K deficiency. The ratio between uncarboxylated (ucOC) and carboxylated (cOC) OC is considered as an indicator of vitamin K status indirectly reflecting arterial calcium. Despite the evidence that OC is an important energy metabolic regulator, its role on global cardio-vascular risk remains unclear. GRP acts as a molecular mediator between inflammation and calcification and may emerge as a novel biomarker playing a key role in these processes. Gla-proteins benefit clinical practice as inhibitors of VC, modifiable by dietary factors.
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Neels, Jaap G., Georges Leftheriotis, and Giulia Chinetti. "Atherosclerosis Calcification: Focus on Lipoproteins." Metabolites 13, no. 3 (March 21, 2023): 457. http://dx.doi.org/10.3390/metabo13030457.
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Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease.
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Laget, Jonas, Sam Hobson, Karen Muyor, Flore Duranton, Irene Cortijo, Piotr Bartochowski, Bernard Jover, et al. "Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study." Cells 12, no. 4 (February 17, 2023): 643. http://dx.doi.org/10.3390/cells12040643.
Full textAbstract:
Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16Ink4a and p21Cip1, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16Ink4a expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD.
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Yang, Rui, Xu Teng, Hui Li, Hong-Mei Xue, Qi Guo, Lin Xiao, and Yu-Ming Wu. "Hydrogen Sulfide Improves Vascular Calcification in Rats by Inhibiting Endoplasmic Reticulum Stress." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/9095242.
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In this study, the vitamin D3plus nicotine (VDN) model of rats was used to prove that H2S alleviates vascular calcification (VC) and phenotype transformation of vascular smooth muscle cells (VSMC). Besides, H2S can also inhibit endoplasmic reticulum stress (ERS) of calcified aortic tissues. The effect of H2S on alleviating VC and phenotype transformation of VSMC can be blocked by TM, while PBA also alleviated VC and phenotype transformation of VSMC that was similar to the effect of H2S. These results suggest that H2S may alleviate rat aorta VC by inhibiting ERS, providing new target and perspective for prevention and treatment of VC.
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Dube, Prabhatchandra, Armelle DeRiso, Mitra Patel, Dhanushya Battepati, Bella Khatib-Shahidi, Himani Sharma, Rajesh Gupta, et al. "Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall." Biomedicines 9, no. 4 (April 8, 2021): 404. http://dx.doi.org/10.3390/biomedicines9040404.
Full textAbstract:
Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.
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Zhao, Yang, Yan Cai, Li-Yan Cui, Wen Tang, Bo Liu, Jia-Jia Zheng, Wen-Zhe Si, Xian Wang, and Ming-Jiang Xu. "Suppression of Gut Bacterial Translocation Ameliorates Vascular Calcification through Inhibiting Toll-Like Receptor 9-Mediated BMP-2 Expression." Oxidative Medicine and Cellular Longevity 2019 (March 17, 2019): 1–12. http://dx.doi.org/10.1155/2019/3415682.
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Aims. Vascular calcification (VC) is a primary risk factor for cardiovascular mortality in chronic renal failure (CRF) patients; thus, effective therapeutic targets are urgently needed to be explored. Here, we identified the role of intestinal bacterial translocation in CRF-related VC. Methods and Results. Antibiotic supplementation by oral gavage significantly suppressed intestinal bacterial translocation, CRF-related VC, and aortic osteogenic gene and Toll-like receptor (TLR) gene expression in CRF rats. Furthermore, TLR4 and TLR9 activation in vascular smooth muscle cells (VSMCs) aggravated inorganic phosphate- (Pi-) induced calcification. TLR9 inhibition, but not TLR4 inhibition, by both a pharmacological inhibitor and genetic methods could significantly reduce CRF rats’ serum or CRF-induced VC. Interestingly, bone morphogenic protein-2 (BMP-2) levels were increased in the aorta and sera from CRF rats. Increased BMP-2 levels were also observed in VSMCs treated with TLR9 agonist, which was blocked by NF-κB inhibition. Both siRNA knockdown of BMP-2 and NF-κB inhibitor significantly blocked TLR9 agonist-induced VSMC calcification. Conclusions. Gut bacterial translocation inhibited by oral antibiotic significantly reduces CRF-related VC through inhibition of TLR9/NF-κB/BMP-2 signaling.
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Xie, Changming, Liu Ouyang, Jie Chen, Huanji Zhang, Pei Luo, Jingfeng Wang, and Hui Huang. "The Emerging Role of Mesenchymal Stem Cells in Vascular Calcification." Stem Cells International 2019 (April 1, 2019): 1–11. http://dx.doi.org/10.1155/2019/2875189.
Full textAbstract:
Vascular calcification (VC), characterized by hydroxyapatite crystal depositing in the vessel wall, is a common pathological condition shared by many chronic diseases and an independent risk factor for cardiovascular events. Recently, VC is regarded as an active, dynamic cell-mediated process, during which calcifying cell transition is critical. Mesenchymal stem cells (MSCs), with a multidirectional differentiation ability and great potential for clinical application, play a duplex role in the VC process. MSCs facilitate VC mainly through osteogenic transformation and apoptosis. Meanwhile, several studies have reported the protective role of MSCs. Anti-inflammation, blockade of the BMP2 signal, downregulation of the Wnt signal, and antiapoptosis through paracrine signaling are possible mechanisms. This review displays the evidence both on the facilitating role and on the protective role of MSCs, then discusses the key factors determining this divergence.
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Jeong, Seongtae, Bok-Sim Lee, Seung Eun Jung, Yoojin Yoon, Byeong-Wook Song, Il-Kwon Kim, Jung-Won Choi, Sang Woo Kim, Seahyoung Lee, and Soyeon Lim. "A Low Concentration of Citreoviridin Prevents Both Intracellular Calcium Deposition in Vascular Smooth Muscle Cell and Osteoclast Activation In Vitro." Molecules 28, no. 4 (February 10, 2023): 1693. http://dx.doi.org/10.3390/molecules28041693.
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Vascular calcification (VC) and osteoporosis are age-related diseases and significant risk factors for the mortality of elderly. VC and osteoporosis may share common risk factors such as renin-angiotensin system (RAS)-related hypertension. In fact, inhibitors of RAS pathway, such as angiotensin type 1 receptor blockers (ARBs), improved both vascular calcification and hip fracture in elderly. However, a sex-dependent discrepancy in the responsiveness to ARB treatment in hip fracture was observed, possibly due to the estrogen deficiency in older women, suggesting that blocking the angiotensin signaling pathway may not be effective to suppress bone resorption, especially if an individual has underlying osteoclast activating conditions such as estrogen deficiency. Therefore, it has its own significance to find alternative modality for inhibiting both vascular calcification and osteoporosis by directly targeting osteoclast activation to circumvent the shortcoming of ARBs in preventing bone resorption in estrogen deficient individuals. In the present study, a natural compound library was screened to find chemical agents that are effective in preventing both calcium deposition in vascular smooth muscle cells (vSMCs) and activation of osteoclast using experimental methods such as Alizarin red staining and Tartrate-resistant acid phosphatase staining. According to our data, citreoviridin (CIT) has both an anti-VC effect and anti-osteoclastic effect in vSMCs and in Raw 264.7 cells, respectively, suggesting its potential as an effective therapeutic agent for both VC and osteoporosis.
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Kwon, Duk-Hwa, Juhee Ryu, Young-Kook Kim, and Hyun Kook. "Roles of Histone Acetylation Modifiers and Other Epigenetic Regulators in Vascular Calcification." International Journal of Molecular Sciences 21, no. 9 (May 4, 2020): 3246. http://dx.doi.org/10.3390/ijms21093246.
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Vascular calcification (VC) is characterized by calcium deposition inside arteries and is closely associated with the morbidity and mortality of atherosclerosis, chronic kidney disease, diabetes, and other cardiovascular diseases (CVDs). VC is now widely known to be an active process occurring in vascular smooth muscle cells (VSMCs) involving multiple mechanisms and factors. These mechanisms share features with the process of bone formation, since the phenotype switching from the contractile to the osteochondrogenic phenotype also occurs in VSMCs during VC. In addition, VC can be regulated by epigenetic factors, including DNA methylation, histone modification, and noncoding RNAs. Although VC is commonly observed in patients with chronic kidney disease and CVD, specific drugs for VC have not been developed. Thus, discovering novel therapeutic targets may be necessary. In this review, we summarize the current experimental evidence regarding the role of epigenetic regulators including histone deacetylases and propose the therapeutic implication of these regulators in the treatment of VC.
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Marreiros, Catarina, Carla Viegas, Anabela Malho Guedes, Ana Paula Silva, Ana Catarina Águas, Marília Faísca, Leon Schurgers, and Dina Costa Simes. "Gla-Rich Protein Is Associated with Vascular Calcification, Inflammation, and Mineral Markers in Peritoneal Dialysis Patients." Journal of Clinical Medicine 13, no. 23 (December 6, 2024): 7429. https://doi.org/10.3390/jcm13237429.
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Background/Objectives: Vascular calcification (VC) is a crucial risk factor for cardiovascular diseases (CVD), particularly in chronic kidney disease (CKD) populations. However, the specific relationship between VC and end-stage renal disease (ESRD) patients undergoing peritoneal dialysis (PD) remains to be fully understood. The identification of new biomarkers to improve VC diagnosis and monitoring would significantly impact cardiovascular risk management in these high-risk patients. Gla-rich protein (GRP) is a VC inhibitor and an anti-inflammatory agent and thus is a potential VC marker in CKD. Here we explored the potential role of GRP as a marker for CVD and investigated the impact of VC in 101 PD patients. Methods: Circulating total Gla-rich protein (tGRP) was quantified in serum and in 24 h dialysate samples. VC score (VCS) was determined using the Adragão method. Results: Serum tGRP was negatively associated with VCS, serum calcium (Ca), phosphate (P), and high-sensitivity C-reactive protein (hsCRP), while it was positively associated with magnesium (Mg). A total of 35.6% of PD patients presented with extensive calcifications (VCS ≥ 3), and the lowest tGRP serum levels were present in this group (419.4 ± 198.5 pg/mL). tGRP in the 24 h dialysate was also negatively associated with VCS and with serum Ca and P. Moreover, serum Ca, P, and VCS were identified as independent determinants of serum tGRP levels. Conclusions: The association of serum tGRP with VC, mineral, and inflammation markers reinforces its potential use as a novel VC biomarker in CKD patients undergoing PD.
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Cannata-Andía, Jorge B., Natalia Carrillo-López, Osvaldo D. Messina, Neveen A. T. Hamdy, Sara Panizo, and Serge L. Ferrari. "Pathophysiology of Vascular Calcification and Bone Loss: Linked Disorders of Ageing?" Nutrients 13, no. 11 (October 27, 2021): 3835. http://dx.doi.org/10.3390/nu13113835.
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Vascular Calcification (VC), low bone mass and fragility fractures are frequently observed in ageing subjects. Although this clinical observation could be the mere coincidence of frequent age-dependent disorders, clinical and experimental data suggest that VC and bone loss could share pathophysiological mechanisms. Indeed, VC is an active process of calcium and phosphate precipitation that involves the transition of the vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Among the molecules involved in this process, parathyroid hormone (PTH) plays a key role acting through several mechanisms which includes the regulation of the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway, the main pathways for bone resorption and bone formation, respectively. Furthermore, some microRNAs have been implicated as common regulators of bone metabolism, VC, left ventricle hypertrophy and myocardial fibrosis. Elucidating the common mechanisms between ageing; VC and bone loss could help to better understand the potential effects of osteoporosis drugs on the CV system.
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Chao, Chia-Ter, and Shih-Hua Lin. "Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins." Toxins 12, no. 12 (December 21, 2020): 812. http://dx.doi.org/10.3390/toxins12120812.
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Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.
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Wang, Xiang, Xinghang Chen, Zhuohui Chen, and Mengqi Zhang. "Arterial Calcification and Its Association With Stroke: Implication of Risk, Prognosis, Treatment Response, and Prevention." Frontiers in Cellular Neuroscience 16 (May 11, 2022). http://dx.doi.org/10.3389/fncel.2022.845215.
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Stroke is a leading cause of death worldwide. Vascular calcification (VC), defined as deposition of calcium-phosphate complexes in the vessels, is considered as the characteristic of vascular aging. Calcifications at different vessel layers have different implications. Intimal calcification is closely related to atherosclerosis and affects plaque stability, while medial calcification can cause arterial stiffening and reduce compliance. Accumulating evidence suggested that arterial calcifications, including calcifications in the intracranial artery, coronary artery, and carotid artery, are associated with the risk, prognosis, and treatment response of stroke. VC can not only serve as a marker of atherosclerosis, but cause cerebral hemodynamic impairment. In addition, calcifications in large arteries are associated with cerebral small vessel disease. In this review, we summarize the findings of recently published studies focusing on the relationship between large artery calcification and the risk, prognosis, treatment response, and prevention of stroke and also discuss possible mechanisms behind those associations.
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Huang, Aoran, Tianhua Xu, Xiaomei Lu, Ling Ma, Haiying Ma, Yanqiu Yu, and Li Yao. "Shh-Gli2-Runx2 inhibits vascular calcification." Nephrology Dialysis Transplantation, July 14, 2023. http://dx.doi.org/10.1093/ndt/gfad165.
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Abstract Background In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC. Methods 2.6 mM inorganic phosphorus was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC. Results Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting vascular calcification (VC). Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with SAG (Hh signaling agonist) showed alleviated VC. And mice treated with CPN (Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B. Conclusions Our study provided deeper insight to the pathogenesis of VC and Shh might be a novel potential target for VC treatment.
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Aierken, Yierpani, Huqiang He, Runwen Li, Zipeng Lin, Tongjie Xu, Li Zhang, Ya Wu, and Yong Liu. "Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells." Cardiovascular Diabetology 23, no. 1 (May 29, 2024). http://dx.doi.org/10.1186/s12933-024-02224-z.
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Abstract Background Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. Methods R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron’s effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. Results Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. Conclusions Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment. Graphical Abstract