Epigenetic regulation of cardiac fibrosis

Abstract

Fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In the heart, fibrosis may be reparative, replacing areas of myocyte loss with a structural scar following infarction, or reactive, which is triggered in the absence of cell death and involves interstitial ECM deposition in response to long-lasting stress. Interstitial fibrosis can increase the passive stiffness of the myocardium, resulting in impaired relaxation and diastolic dysfunction. Additionally, fibrosis can lead to disruption of electrical conduction in the heart, causing arrhythmias, and can limit myocyte oxygen availability and thus exacerbate myocardial ischemia. Here, we review recent studies that have illustrated key roles for epigenetic events in the control of pro-fibrotic gene expression, and highlight the potential of small molecules that target epigenetic regulators as a means of treating fibrotic cardiac diseases.

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

“…TGFβ drives the fibrotic process by binding to the heterodimeric membrane receptor, which results in phosphorylation and subsequent nuclear translocation of the SMAD family of transcription factors. Thus, inhibition of the specific cellular receptors, kinases and other mediators involved in activation of the TGFβ pathway may provide effective therapeutic targets for treating cardiac fibrosis 45, 46 . Impedance of cellular differentiation and Smad2/3 phosphorylation by IL10 suggests that IL10 holds pertinent therapeutic potential for treatment of heart failure by its strong inhibitory role in BM-FPC-mediated fibrosis in pressure-overloaded myocardium.…”

Therapeutic Potential for Natural Product HDAC Inhibitors in Heart Failure

“…extensively [4,6,7,11,34,35]. Treatment with pan-HDAC inhibitors such as TSA, for instance, have been shown to block and even reverse cardiac hypertrophy and systolic dysfunction in rodent models of aortic constriction.…”

The Potential of Targeting Epigenetic Regulators for the Treatment of Fibrotic Cardiac Diseases

“…The reasons for this surge in interest are fourfold: (i) increased ability to non-invasively detect cardiac fibrosis through advanced imaging tools; (ii) establishment of clear correlations between cardiac fibrosis and clinical outcomes; (iii) essentially a complete lack of effective anti-fibrotic treatment options, creating a heightened awareness of this massive unmet medical need; and (iv) increasing recognition that the heart is a complex mixture of heterogeneous, interacting cell types, rather than simply a pump consisting only of myocytes [1]. It is our view that epigenetic regulators, which govern gene expression via modifications of nucleosomal DNA and protein, are among the most auspicious [2] and underappreciated [3] therapeutic targets for the treatment of pathological cardiac fibrosis.…”

“…Pan-, hydroxamic acid-based HDAC inhibitors have long been known to suppress cardiac fibrosis [9] and, more recently, isoform-selective HDAC inhibitors were employed to demonstrate a role for class I HDACs (HDAC1, -2 and -3) in the control of cardiac fibrosis [2,[10][11]. In one example, the benzamide class I HDAC inhibitor mocetinostat blunted progression of pre-existing cardiac fibrosis in a rat myocardial infarction model [10].…”

“…However, endomyocardial biopsies would not be justified in healthy subjects due to unwarranted risk. We recently proposed a potentially attractive solution that would pose less risk to patients [2]. Patients scheduled to undergo surgery to implant a left ventricular assist device (LVAD) as a 'bridge-to-transplant' measure would be attractive candidates for Phase I clinical trials of epigenetic therapies.…”