Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype

Abstract

Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-term adaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process. This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1% hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1α. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2'-deoxycytidine suppressed the pro-fibrotic effects of TGFβ. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.

Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction

“…An upregulation and increased secretion of miR-29a, as a secondary effect of Dnmt3a inhibition in modified CPCs, may participate to the beneficial antifibrotic effect we observed in vivo. Moreover, in human cardiac tissue, profibrotic changes induced by prolonged hypoxia during MI are associated with a global DNA hypermethylation and increased expression of Dnmt1 and Dnmt3b enzymes (42). Indeed, Dnmt3-induced hypermethylation of antifibrotic genes, such as THY-1 (43) or RASSF1A (44), was shown to contribute to fibroblast activation and fibrogenesis.…”

DNA methylation in fibrosis

“…Thus, TGF-β can induce both hypermethylation and hypomethylation, illustrating the complexities of the pathways that control and alter methylation patterns. Interestingly, treatment with 5-aza-2'-deoxycytidine abrogates the effects of TGF-β induced myofibroblasts in cardiac cells (Watson et al, 2014).…”

Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes?

“…It has found a sufficient difference in DNA methylation in promoters of up-regulated genes, but not down-regulated genes in end-stage cardiomyopathy [40]. Furthermore, the process of DNA methylation was under regulation through several genetic pathways that are modulating by platelet/ endothelial cell adhesion molecule 1, hypoxia-inducible factor1alpha, angiomotin-like 2, and Rho GTPase activating protein 24 [40,41] . Authors suggested that epigenetic modifications identified in failing heart might affect cardiac function directly through regulation of structure protein synthesis and, however, indirectly via increased activity of cardiac fibroblasts due to prolonged hypoxia contributing to the pro-fibrotic nature of the ischemic milieu.…”