Targeting cardiac fibroblasts to treat fibrosis of the heart: focus on HDACs

Abstract

Cardiac fibrosis is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure and cardiac arrhythmias. However the specific cells and signaling pathways mediating this process are poorly understood. Lysine acetylation of nucleosomal histone tails is an important mechanism for the regulation of gene expression. Additionally, proteomic studies have revealed that thousands of proteins in all cellular compartments are subject to reversible lysine acetylation, and thus it is becoming clear that this post-translational modification will rival phosphorylation in terms of biological import. Acetyl groups are conjugated to lysine by histone acetyltransferases (HATs) and removed from lysine by histone deacetylases (HDACs). Recent studies have shown that pharmacologic agents that alter lysine acetylation by targeting HDACs have the remarkable ability to block pathological fibrosis. Here, we review the current understanding of cardiac fibroblasts and the fibrogenic process with respect to the roles of lysine acetylation in the control of disease-related cardiac fibrosis. Potential for small molecule HDAC inhibitors as anti-fibrotic therapeutics that target cardiac fibroblasts is highlighted. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium."

Keywords: Epigenetics; Fibroblast; Fibrosis; Histone acetylation.

Figure 1. Processes mediating the development of cardiac fibrosis

Cardiac fibrosis is triggered by diverse cues, including mechanical stress, myocyte death and inflammation. Shown are representative images of left ventricles stained with picrosirius red dye to assess interstitial fibrosis from an untreated mouse (left image) and a mouse treated with angiotensin II (Ang II) for two weeks. Pharmacologic inhibition of class I HDACs blocks development of Ang II-mediated cardiac fibrosis. Under normal conditions, resident cardiac fibroblasts contribute to various homeostatic mechanisms in the heart, including maintenance of structural integrity, electromechanical coupling and angiogenesis. Development of pathological cardiac fibrosis is dependent on differentiation of resident cardiac fibroblasts, as well as other cell types listed, into phenotypically and functionally distinct myofibroblasts, which contribute to arrhythmias, ischemia and diastolic dysfunction.

Figure 2. HDAC classification and selectivity of inhibitors

(A) Class I HDACs include HDAC1, -2, -3 and -8. Class II HDACs are divided into IIa, HDAC4, -5, -7, -9, and IIb, consisting of HDAC6 and -10. Class III HDACs are also referred to as sirtuins (SIRT) and include SIRT1-7. HDAC11 represents the only class IV HDAC. Class III HDACs require NAD+ for catalytic activity while the all other HDACs are zinc-dependent (outlined in blue). (B) Routinely used and available HDAC inhibitors target class I, IIb and IV HDACs by chelating zinc in the active sites of the enzymes. Shown are the selectivity profiles for the anti-fibrotic HDAC inhibitors highlighted in this review: trichostatin A (TSA), SAHA, valproic acid (VPA) and MGCD0103.

Figure 3. Mechanisms by which class I HDAC inhibition blocks cardiac fibrosis

Class I HDAC inhibition prevents the differentiation of bone-marrow derived fibrocytes into active fibrocytes and fibroblasts through inhibition of ERK1/2 activation. Class I HDAC inhibition arrests cardiac fibroblasts in G₀/G₁ of the cell cycle via upregulation of the cyclin-dependent kinase (CDK) inhibitors p15 and p57. Both of these processes result in decreased numbers of activated ECM-producing fibroblasts and myofibroblasts in the myocardium, leading to decreased fibrosis.