scholarly journals Inflammatory, Metabolic, and Genetic Mechanisms of Vascular Calcification

2014 ◽  
Vol 34 (4) ◽  
pp. 715-723 ◽  
Author(s):  
Linda L. Demer ◽  
Yin Tintut

This review centers on updating the active research area of vascular calcification. This pathology underlies substantial cardiovascular morbidity and mortality, through adverse mechanical effects on vascular compliance, vasomotion, and, most likely, plaque stability. Biomineralization is a complex, regulated process occurring widely throughout nature. Decades ago, its presence in the vasculature was considered a mere curiosity and an unregulated, dystrophic process that does not involve biological mechanisms. Although it remains controversial whether the process has any adaptive value or past evolutionary advantage, substantial advances have been made in understanding the biological mechanisms driving the process. Different types of calcific vasculopathy, such as inflammatory versus metabolic, have parallel mechanisms in skeletal bone calcification, such as intramembranous and endochondral ossification. Recent work has identified important regulatory roles for inflammation, oxidized lipids, elastin, alkaline phosphatase, osteoprogenitor cells, matrix γ-carboxyglutamic acid protein, transglutaminase, osteoclastic regulatory factors, phosphate regulatory hormones and receptors, apoptosis, prelamin A, autophagy, and microvesicles or microparticles similar to the matrix vesicles of skeletal bone. Recent work has uncovered fascinating interactions between matrix γ-carboxyglutamic acid protein, vitamin K, warfarin, and transport proteins. And, lastly, recent breakthroughs in inherited forms of calcific vasculopathy have identified the genes responsible as well as an unexpected overlap of phenotypes. Until recently, vascular calcification was considered a purely degenerative, unregulated process. Since then, investigative groups around the world have identified a wide range of causative mechanisms and regulatory pathways, and some of the recent developments are highlighted in this review.

2009 ◽  
Vol 85 (4) ◽  
pp. 864-873 ◽  
Author(s):  
Yan Cai ◽  
Ming-Jiang Xu ◽  
Xu Teng ◽  
Ye Bo Zhou ◽  
Li Chen ◽  
...  

Toxins ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 624 ◽  
Author(s):  
Nikolas Rapp ◽  
Pieter Evenepoel ◽  
Peter Stenvinkel ◽  
Leon Schurgers

The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification.


Author(s):  
John R Burnett ◽  
Samuel D Vasikaran

Atherosclerotic heart disease and osteoporosis are both diseases of old age. Evidence is accumulating for a link between vascular and bone disease. Calcification is a common feature of atherosclerotic plaques, and osteoporosis is associated with both atherosclerosis and vascular calcification. However, the relationship of vascular calcification to the pathogenesis of atherosclerosis remains incompletely understood. Hormone replacement therapy has beneficial effects in the prevention of both atherosclerosis and osteoporosis. Bisphosphonates inhibit bone resorption and are used in the treatment of osteoporosis, whereas the statins inhibit cholesterol biosynthesis and are used for the treatment of atherosclerosis. We have reviewed recent advances in the knowledge of the actions of bisphosphonates and statins at the cellular, molecular and end-organ levels in order to examine the relationship between cardiovascular disease and osteoporosis and to explore the link between lipids and bones. These studies suggest that the mechanism of actions of these two classes of drugs at the cellular level may not be mutually exclusive. There are some early clinical data to complement these findings, suggesting that statins increase bone density and bisphosphonates may have a beneficial effect in vivo on plasma lipid levels and on the atherosclerotic process. Properly designed prospective studies that examine the effect of statins on bone density and fractures, as well as the effects of bisphosphonates on lipid profiles, atherosclerotic progression and cardiovascular morbidity and mortality are needed to define clearly the clinical effects and potential new roles for these agents.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takehisa Shimizu ◽  
Toru Tanaka ◽  
Tatsuya Iso ◽  
Masahiko Kurabayashi

Vascular calcification is a prominent feature of atherosclerosis and closely correlated with cardiovascular morbidity and mortality. In this study, we hypothesize that Notch signaling plays an important role in osteogenic conversion of smooth muscle cells (SMCs) and vascular calcification. <Methods and Results> Either Notch ligand-expressing cells or overexpression of Notch intracellular domains (NICDs) induced expression of Msx2, a key regulator of osteogenic conversion, in human aortic SMCs (HASMCs). In addition, overexpression of Notch1 intracellular domain (N1-ICD) markedly upregulated alkaline phosphatase (ALP) activity and matrix mineralization of HASMCs. A knockdown experiment with a small interfering RNA confirmed that Msx2, but not Runx2/Cbfa1, another key osteogenic transcription factor, is responsible for Notch1-induced osteogenic conversion of HASMCs. Furthermore, this Notch1-Msx2 pathway was independent of bone morphogenetic protein-2 (BMP-2), an osteogenic morphogen upstream of Msx2. The transcriptional activity of the Msx2 promoter was significantly enhanced by Notch ligands stimulation, whereas it was abrogated by a specific Notch signaling inhibitor. The RBP-Jk binding element within the Msx2 promoter was critical to Notch1-induced Msx2 gene expression, and correspondingly, neither N1-ICD overexpression nor Notch ligands stimulation increase the Msx2 expression or transcriptional activity of the Msx2 promoter, respectively, in RBP-Jk-deficient fibroblasts. Immunohistochemistry of human artery specimens revealed colocalization of Notch1 and Msx2 within atherosclerotic plaques, indicating a role of Notch1-Msx2 pathway in vascular calcification in vivo. These results suggest that Notch signaling directly targets Msx2, thus accelerating osteogenic conversion of HASMCs and, as a result, a formation of vascular calcification.


2009 ◽  
Vol 39 (3) ◽  
pp. 183-194 ◽  
Author(s):  
Gerardo M. Nava ◽  
David Y. Lee ◽  
Javier H. Ospina ◽  
Shi-Ying Cai ◽  
H. Rex Gaskins

The major thiol redox buffer glutathione (l-γ-glutamyl-l-cysteinylglycine, GSH) is central to cell fate determination, and thus, associated metabolic and regulatory pathways are exquisitely sensitive to a wide range of environmental cues. An imbalance of cellular redox homeostasis has emerged as a pathologic hallmark of a diverse range of human gene-environment disorders. Despite the central importance of GSH in cellular homeostasis, underlying genetic regulatory pathways remain poorly defined. This report describes the annotation and expression analysis of genes contributing to GSH homeostasis in the invertebrate chordate Ciona intestinalis . A core pathway comprising 19 genes contributing to the biosynthesis of GSH and its use as both a redox buffer and a conjugate in phase II detoxification as well as known transcriptional regulators were analyzed. These genes exhibit a high level of sequence conservation with corresponding human, rat, and mouse homologs and were expressed constitutively in tissues of adult animals. The GSH biosynthetic genes Gclc and Gclm were also responsive to the prototypical antioxidant tert-butylhydroquinone. The present evidence of a conserved GSH homeostasis pathway in C. intestinalis together with its phylogenetic position as a basal chordate and lifestyle as a filter feeder constantly exposed to natural marine toxins introduces this species as an important animal model for defining molecular mechanisms that potentially underlie genetic susceptibility to environmentally associated stress.


2018 ◽  
Author(s):  
Romain Laurian ◽  
Karine Dementhon ◽  
Bastien Doumèche ◽  
Alexandre Soulard ◽  
Thierry Noel ◽  
...  

AbstractMetabolic flexibility promotes infection and commensal colonization by the opportunistic pathogenCandida albicans.Yeast cell survival depends upon assimilation of fermentable and non-fermentable locally available carbon sources. Physiologically relevant sugars like glucose and fructose are present at low level in host niches. However, because glucose is the preferred substrate for energy and biosynthesis of structural components, its efficient metabolization is fundamental for the metabolic adaptation of the pathogen. We explored and characterized theC. albicanshexose kinase system composed of one hexokinase (CaHxk2) and two glucokinases (CaGlk1 and CaGlk4). Using a set of mutant strains, we found that hexose phosphorylation is mostly assured by CaHxk2, which sustains growth on hexoses. Our data on hexokinase and glucokinase expression point out an absence of cross regulation mechanisms at the transcription level and different regulatory pathways. In the presence of glucose, CaHxk2 migrates in the nucleus and contributes to the glucose repression signaling pathway. In addition, CaHxk2 participates to oxidative, osmotic and cell wall stress responses, while glucokinases are overexpressed under hypoxia. Hexose phosphorylation is a key step necessary for filamentation, that is affected in the hexokinase mutant. Virulence of this mutant is clearly impacted in theGalleria mellonellaand macrophage models. Filamentation, glucose phosphorylation and stress response defects of the hexokinase mutant prevent host killing byC. albicans.By contributing to metabolic flexibility, stress answer response and morphogenesis, hexose kinase enzymes play an essential role in the virulence ofC. albicans.Author summaryThe pathogenic yeastC. albicansis both a powerful commensal and pathogen of humans that can infect wide range of organs and body sites. To grow in its host and establish an infection, the pathogen must assimilate carbon from these heterogenous environments.C. albicansregulates central carbon metabolism in a niche-specific manner, activating alternatively gluconeogenesis, glyoxylate cycle and the glycolytic metabolism. For yeast and other microorganisms, glucose is the preferred carbon and energy source and its accurate detection and metabolism is essential. However, the glycolytic hexose kinase system has not been investigated yet inC. albicans.In this report, we showed that hexokinase and glucokinases contribute to the fitness and virulence ofC. albicans.We revealed the main metabolic role of the hexokinase CaHxk2 which impacts on growth, glucose signalling, morphological transition and virulence. However, glucokinases contribute to the anoxic response and their implication in regulation processes is suggested.


2021 ◽  
Vol 8 ◽  
Author(s):  
Guozhen Yuan ◽  
Jingjing Shi ◽  
Qiulei Jia ◽  
Shuqing Shi ◽  
Xueping Zhu ◽  
...  

Cardiovascular disease (CVD) is a serious threat to global public health due to its high prevalence and disability rate. Meanwhile, cardiac rehabilitation (CR) has attracted increasing attention for its positive effects on the cardiovascular system. There is overwhelming evidence that CR for patients with CVD is effective in reducing cardiovascular morbidity and mortality. To learn more about the development of CR, 5,567 papers about CR and related research were retrieved in the Web of Science Core Collection from 2001 to 2020. Then, these publications were scientometrically analyzed based on CiteSpace in terms of spatiotemporal distribution, author distribution, subject categories, topic distribution, and references. The results can be elaborated from three aspects. Firstly, the number of annual publications related to CR has increased year by year in general over the past two decades. Secondly, a co-occurrence analysis of the output countries and authors shows that a few developed countries such as the United States, Canada, and the UK are the most active in carrying out CR and where regional academic communities represented by Sherry Grace and Ross Arena were formed. Thirdly, an analysis of the subject categories and topic distribution of the papers reveals that CR is a typical interdiscipline with a wide range of disciplines involved, including clinical medicine, basic medicine, public health management, and sports science. The research topics cover the participants and implementers, components, and the objectives and requirements of CR. The current research hotspots are the three core modalities of CR, namely patient education, exercise training and mental support, as well as mobile health (mHealth) dependent on computer science. In conclusion, this work has provided some useful information for acquiring knowledge about CR, including identifying potential collaborators for researchers interested in CR, and discovering research trends and hot topics in CR, which can offer some guidance for more extensive and in-depth CR-related studies in the future.


Author(s):  
Daniel Butt

This chapter examines the limitations of both command-and-control and market-based legal mechanisms in the pursuit of environmental justice. If the environment is to be protected to at least a minimally acceptable degree, approaches that focus on the coercive force of the state must be complemented by the development of an “ecological ethos,” whereby groups and individuals are motivated to act with non-self-interested concern for the environment. The need for this ethos means that the state is dependent on the cooperation of a wide range of non-state actors. Recent work on environmental governance emphasizes the delegation of aspects of governing to such actors and supports efforts to increase popular participation in governmental processes. The chapter therefore advocates a governance approach that seeks to rectify some of the limitations of state-led environmental law, while encouraging popular participation in a way that can encourage the development of an ecological ethos among the citizenry.


Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 737 ◽  
Author(s):  
Hyun-Joo Park ◽  
Yeon Kim ◽  
Mi-Kyoung Kim ◽  
Jae Joon Hwang ◽  
Hyung Joon Kim ◽  
...  

Vascular calcification is the pathological deposition of calcium/phosphate in the vascular system and is closely associated with cardiovascular morbidity and mortality. Here, we investigated the role of gastrin-releasing peptide (GRP) in phosphate-induced vascular calcification and its potential regulatory mechanism. We found that the silencing of GRP gene and treatment with the GRP receptor antagonist, RC-3095, attenuated the inorganic phosphate-induced calcification of vascular smooth muscle cells (VSMCs). This attenuation was caused by inhibiting phenotype change, apoptosis and matrix vesicle release in VSMCs. Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification.


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