Abstract
Thyroid hormone (TH) signaling is critically involved in the regulation of cardiovascular physiology. Even mild reductions of myocardial TH levels, as occur in hypothyroidism or low T3 state conditions, are thought to play a role in the progression of cardiac disorders. Due to recent advances in molecular mechanisms underlying TH action, it is now accepted that TH-dependent modulation of gene expression is achieved at multiple transcriptional and post-transcriptional levels and involves the cooperation of many processes. Among them, the epigenetic remodeling of chromatin structure and the interplay with non-coding RNA have emerged as novel TH-dependent pathways that add further degrees of complexity and broaden the network of genes controlled by TH signaling. Increasing experimental and clinical findings indicate that aberrant function of these regulatory mechanisms promotes the evolution of cardiac disorders such as post-ischemic injury, pathological hypertrophy, and heart failure, which may be reversed by the correction of the underlying TH dyshomeostasis. To encourage the clinical implementation of a TH replacement strategy in cardiac disease, here we discuss the crucial effect of epigenetic modifications and control of non-coding RNA in TH-dependent regulation of biological processes relevant for cardiac disease evolution.
Highlights
Remodeling of cardiac tissue architecture is the common denominator of a variety of cardiovascular pathologies including myocardial infarction, coronary artery disease, hypertension, cardiomyopathy, and arrhythmias [1]
heart failure (HF) evolution is characterized by a maladaptive down-regulation of the adult cardiac muscle proteins isoforms such as alpha myosin heavy chain and sarcoplasmic reticulum Ca2+ATPase 2a (Serca2a) and a concomitant up-regulation of the fetal genes such as beta myosin heavy chain and phospholamban (Pln) [2]
These authors revealed that T3-dependent down-regulation of Pln in cardiac myocytes is mediated by THRA1 and involves the hormone-directed recruitment of histone deacetylases (HDACs) and histone demethylase (HDM) activities to decrease both histone H3 acetylation and H3K4met epigenetic marks [90]
Summary
Remodeling of cardiac tissue architecture is the common denominator of a variety of cardiovascular pathologies including myocardial infarction, coronary artery disease, hypertension, cardiomyopathy, and arrhythmias [1]. The physiological purpose of these coordinated cellular events is to repair damaged tissue and preserve cardiac performance, persistent activation of the wound healing process is detrimental and facilitates the progression to heart failure (HF). HF evolution is characterized by a maladaptive down-regulation of the adult cardiac muscle proteins isoforms such as alpha myosin heavy chain (αMHC) and sarcoplasmic reticulum Ca2+ATPase 2a (Serca2a) and a concomitant up-regulation of the fetal genes such as beta myosin heavy chain (βMHC) and phospholamban (Pln) [2]
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