1,721,015 research outputs found
Origins of Cardiac Fibroblasts
No full textCardiac fibroblasts play a critical role in maintenance of normal cardiac function. They are indispensable for damage control and tissue remodeling on myocardial injury and principal mediators of pathological cardiac remodeling and fibrosis. Despite their manyfold functions, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that cardiac fibroblasts are a heterogeneous population and likely derive from various distinct tissue niches in health and disease. Here, we review our emerging understanding of where cardiac fibroblasts come from, as well as how we can possibly use this knowledge to develop novel therapies for cardiac fibrosis.</jats:p
The role of promoter hypermethylation in fibroblast activation and fibrogenesis
No full textThe aberrant methylation of CpG island promoters of selected genes is the prominent epigenetic mechanism by which gene transcription can be effectively silenced. Aberrant hypermethylation of a few selected genes plays an important role in facilitating fibrotic fibroblast activation and in driving fibrogenesis. Here we review mechanisms of DNA methylation and demethylation and their implications for fibroblast activation and tissue fibrosis
Precision renal medicine: a roadmap towards targeted kidney fibrosis therapies
No full textBased on extensive pre-clinical achievements over the past decades, it appears to be due time for a successful clinical translation in the renal fibrosis field—but what is the quickest road to get there? In light of the recent launch of the Precision Medicine Initiative and success of molecularly informed drugs in oncology, we here discuss what it may take to bring molecularly targeted anti-fibrotic to clinical use in chronic progressive kidney disease
High Phosphate Induces Endothelial-Mesenchymal Transition of Human Coronary Endothelial Cells by Epigenetic Regulation of DNMT1: a Link from Chronic Kidney to Cardiovascular Disease
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High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation
No full textPhosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that high inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of alpha-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho-regulatory hormones. (C) 2016 Published by Elsevier Inc
High Phosphate Induces Endothelial-Mesenchymal Transition of Human Coronary Endothelial Cells by Epigenetic Regulation of DNMT1: a Link from Chronic Kidney to Cardiovascular Disease
No full textAssociation of circulating angiogenesis inhibitors and asymmetric dimethyl arginine with coronary plaque burden
No full textBackground Chronic kidney disease (CKD) is an independent risk factor for the development and severity of coronary artery disease (CHD) and endothelial dysfunction. There is an increase in the circulating angiogenesis inhibitors endostatin (END), thrombospondin-2 (TSP), angiopoietin-2 (ANG) and the nitric oxide (NO) inhibitor asymmetric dimethyl arginine (ADMA) in CKD patients. The aim of this study was to evaluate associations of the serum level of these factors and of the related angiogenesis inhibitor, endoglin (ENG), with burden of coronary atherosclerosis. Methods One hundred twenty-two patients undergoing coronary angiography were recruited from the cardiac catheterization lab at a single center. The total burden of coronary plaque (mm2) and the presence of coronary collaterals were quantified using quantitative coronary angiography (QCA). Serum levels of angiogenesis inhibitors were measured by ELISA (ENG, END, and ANG), Luminex assay (TSP), or HLPC (ADMA), respectively. Associations with plaque burden and coronary collateral supply were analyzed in multi-variable linear and logistic regression models. Results There was no significant association found between levels of circulating ADMA, ENG, END, ANG, or TSP and coronary plaque burden or collateral formation. Conclusions Our findings suggest that associations of circulating END, ENG, TSP, and ANG with cardiovascular mortality are unlikely to be mediated via direct effects on coronary plaque formation or by inhibition of collateral formation. Whether associations of these factors with mortality are mediated via local concentrations, myocardial tissue, or intra-plaque expression of these factors or by an effect on plaque vulnerability merits additional investigation
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