Epigenetic Regulation of Myocardial Homeostasis, Self-Regeneration and Senescence

Abstract

The adult myocardium has limited capacity to preserve, renew or rejuvenate itself. The local microenvironment may induce epigenetic changes affecting the survival, proliferation, function and senescence of cardiac cells at rest and following the exposure to different stressors. The cellular response to microenvironment is characterized by the release of ions, oxygen free radicals, auto/paracrine factors and RNAs that drive the magnitude of gene reprogramming through the interaction with specific promoters. The epigenetic alterations may act at transcriptional and post-transcriptional level and change cardiac physiological traits. The abnormal DNA methylation underlies the progressive decay of contractile function and the angiogenic ability; while, the histone acetylation promotes the survival, function and proliferation of cardiac cells in the presence of ischemic microenvironment. At least, the expression and secretion of microRNAs and long noncoding RNAs may regulate the threshold to stress tolerance of adult cardiac cells and induce the matrix turnover as well. Natural or synthetic active compounds effectively modulate the epigenetic state of cardiac cells. Plant foods contain many active compounds with epigenetic properties and might assume a clinical significance as natural cardiac regenerators or rejuvenators. Our review describes novel epigenetic mechanisms that underpin myocardial remodeling, repair/ regeneration or senescence in order to support the development of most effective and reproducible rescue therapy of adult heart.

Regulation of the Adaptive Response of Cardiac Cells to Ischemia: Role of Nanovesicles

“…Interestingly, we have demonstrated that porcine aortic endothelial cells co-cultured with porcine adipose-derived mesenchymal stem cells (MSCs) under normoxic conditions release increasing amount of exosomes delivering hypoxiainducible factor 1-alpha (HIF1-alpha), in a time dependentmanner [71]. The exosomal release was directly related to the accumulation of free radicals into the culture medium.…”

The Unexpected Cardioprotection by Epigenetic Foods

“…DNA methylation refers mainly to the addition of a methyl group to the 5-position of cytosine of CpG sequence of promoter regulatory regions through selective enzymes [5]. The cells use DNA methylation to lock gene trascription in the off position by three mechanisms: i) the blocking of recruitment of transcription factors to correspondent cis-DNA binding elements by steric hindrance, ii) the specific co-binding of proteins to methylated DNA that compete with the specific transcriptional factors [53] and iii) the recruitment of histone deacetylases (HDACs) to silence gene expression [54].…”

“…Histone modifications alter the gene expression through changes in the nucleosome conformation in ). Histones undergo to different posttranslational modifications at level of lysine (acetylation, ubiquitination, methylation, sumolyation) or arginine (methylation) or serine and threonine (phosphorylation) residues [5]. Reversible histone acetylation plays a key role in the development of postischemic myocardial remodelling.…”

“…MicroRNA (miRNAs) and the RNA interference machinery are endogenous key repressors of chromatinbased gene expression [5]. Most miRNAs genes are located at level of the intergenic, intronic, or exonic regions of DNA and are transported from the nucleus to the cytoplasm as part of mRNA.…”

“…Therefore, it is clinically relevant to address further studies to dissect alternative pathophysiological issues, such as cellto-cell and cell-to-microenvironment cross-talk during the exposure to ischemic insult. Epigenetic modifications mediate mechanisms underline cellular tolerance against ischemic microenvironment, as cell survival and angiogenesis [5]. Despite the threshold of adaptive epigenetic effects is difficult to be safely modulated by synergistic drug combinations, the intramyocardial delivery of low doses of specific natural compounds has protected the ischemic myocardium through the modification of the epigenetic profile of cardiomyocytes, endothelial and interstitial cells [6].…”