Epigenetic Mechanisms of Endothelial Progenitor Cell Dysfunction

Abstract

Diabetes mellitus remains a leading factor contributing increased morbidity and mortality worldwide. The development and progression of DM associates with microvascular and macrovascular complications linked the DM with cardiovascular events. The impaired ability of endothelium to repair the injury and restore integrity depends in part on number and function of endothelial progenitor cells (EPCs). The mechanisms underlying EPC dysfunction in DM predominantly include weak bone marrow mobilization, decreased proliferation, and shortened survival. The weak function and lowered number of EPCs obtained from peripheral blood were recently found in 1 type and 2 type of DM. It has suggested that glucose toxicity, lipid toxicity, inflammation and oxidative stress may directly and indirectly via several molecular mechanisms worse of EPCs function and, however, lead to deficiency of circulating angiopoetic progenitors. Epigenetic changes are considered important key to understand whether EPCs dysfunction is reversible setting or not. The aim of editorial is to discuss around the role of epigenetic changes in EPCs in linking of DM with cardiovascular risk. Keywords: Diabetes mellitus; Endothelial progenitor cells; Endothelial dysfunction; Endothelial injury; Impaired vascular reparation; Cardiovascular risk EditorialDiabetes mellitus (DM) is a major metabolic factor leading to increased mortality and morbidity associated with higher incidence of disability, huge social and economic burden [1,2]. Recent basic and clinical studies have shown that development and progression of DM has impaired endothelium structure and integrity via several molecular mechanisms induced by glucose toxicity, lipid toxicity, oxidative stress, and inflammation [3][4][5][6]. On this way, epigenetic changes affected function and structure of endothelial-derived progenitor cells (EPCs) might lead to worsening of endothelium reparation [7]. Moreover, the EPCs dysfunction might be a clue in the initiation of DM-related microvascular and macrovascular complications [8,9] having a great predictive value [9].EPCs originated from bone marrow cells and peripheral blood cells support endothelial homoeostasis and attenuate angiogenesis. The mechanisms underlying EPC dysfunction in DM predominantly include weak bone marrow mobilization, decreased proliferation, and shortened survival [10]. Importantly, the deregulation of epigenetic features of EPCs plays a key role in DM-induced vascular injury and endothelial dysfunction [11]. DNA methylation / hydroxymethylation / transmethylation, histone modifications, and differential expression of specific non-coding RNAs like microRNA (miRNAs) are discussed as causative mechanisms of epigenetic modifications [12]. Despite this, the early phases of epigenetically changes in EPCs are pre-diabetic situation affected mitochondrial injury upon hyperglycemic insult, oxidative stress activation, and lowering survival ability of cell organelles [13]. Indeed, lowered cell membrane protection against hyperglycemic endoth...

Endogenous Stem Cells in Homeostasis and Aging

“…H3K36me3 methyltransferase is required for vascular development, endothelial cell differentiation, and function [130]. Epigenetic changes in EPCs with increased H3K4m3 and reduced H3K9me3 induce the secretion of pro-inflammatory cytokines such as MCP-1 and IL-6 and impair the angiopoietic phenotype, which leads to increased risk for cardiovascular disease [131].…”

Cysteine Glutathionylation Acts as a Redox Switch in Endothelial Cells

“…The modification of histone methylation state plays a key role in EC function by acting upstream of gene transcription, and its implications in cardiovascular pathologies [76]. Importantly, epigenetics appears as an essential player in EC progenitor function, therefore regulating vascular repair processes [77,78]. Histone modifications are particularly important for regulating the expression of key EC genes as the endothelial nitric oxide synthase (eNOS) and the vascular endothelial growth factor 1 (VEGFR1), therefore playing a pivotal role in vascular homeostasis and angiogenesis (Figure 3a) [79,80,81].…”

“…Beyond the regulation of vascular barrier integrity, further understanding of Rho GTPase redox regulation could provide important insights on EC response to oxidative stress through NADPH oxidase and eNOS activation [36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,…”

Novel Biomarkers for Cardiovascular Risk in Obese Patients

“…Outgrowth endothelial progenitors as a subpopulation of EPCs exhibit a protective impact on the endothelium mediating proliferation and having the ability to promote angiogenesis and collateral vessel growth [24] . These processes are under closely paracrine and epigenetic regulation affected in particularly migration, proliferation, and mobilization of EPCs from bone marrow and peripheral tissues [25,26] .…”