Non-sirtuin histone deacetylases in the control of cardiac aging

Abstract

Histone deacetylases (HDACs) catalyze the removal of acetyl-groups from lysine residues within nucelosomal histone tails and thousands of non-histone proteins. The 18 mammalian HDACs are grouped into four classes. Classes I, II and IV HDACs employ zinc as a co-factor for catalytic activity, while class III HDACs (also known as sirtuins) require NAD+ for enzymatic function. Small molecule inhibitors of zinc-dependent HDACs are efficacious in multiple pre-clinical models of pressure overload and ischemic cardiomyopathy, reducing pathological hypertrophy and fibrosis, and improving contractile function. Emerging data have revealed numerous mechanisms by which HDAC inhibitors benefit the heart, including suppression of oxidative stress and inflammation, inhibition of MAP kinase signaling, and enhancement of cardiac protein aggregate clearance and autophagic flux. Here, we summarize recent findings with zinc-dependent HDACs and HDAC inhibitors in the heart, focusing on newly described functions for distinct HDAC isoforms (e.g. HDAC2, HDAC3 and HDAC6). Potential for pharmacological HDAC inhibition as a means of treating age-related cardiac dysfunction is also discussed. This article is part of a Special Issue entitled: CV Aging.

Keywords: Aging; Heart failure; Histone deacetylase.

Figure 1. Zinc-dependent HDACs and cardiac aging

(A) Zinc-dependent HDACs fall into three classes, with class II being subdivided into IIa and IIb. Class III HDACs (sirtuins), which are NAD+-dependent, are not shown. (B) In response to hypertrophic stimuli, HDAC2 is acetylated by p300/CBP-associated factor (PCAF), which primes the protein for phosphorylation by casein kinase 2 (CK2). Acetylated and phosphorylated HDAC2 is more active, and thus has increased capacity to repress anti-hypertrophic gene expression. Hypertrophic signals also lead to HDAC3-mediated repression of the gene encoding dual-specificity phosphatase 5 (DUSP5). In HDAC inhibitor-treated cardiomyocytes, DUSP5 expression increases, creating a negative feedback loop that blocks pro-hypertrophic ERK signaling in the nucleus.

Figure 2. Newly described regulation and function of class II HDACs in the heart

Class IIb HDAC6 contains tandem deacetylase domains, a cytoplasmic anchor and a ubiquitin binding motif. Roles of HDAC6 in cardiac disease have only recently been described, and include impairment of contractile function, promotion of protein aggregate formation, and atrial myocyte remodeling and atrial fibrillation propagation. Class IIa HDAC4 represses pro-hypertrophic gene expression in the heart by promoting formation of repressive methylation marks on histone H3 lysine-9 (H3K9). HDAC4 is recruited to pro-hypertrophic genes through association with the DNA binding transcription factor myocyte enhancer factor 2 (MEF2). This complex also contains the methyl-histone binding protein HP1 and the histone methyltransferase SUV39H1. In response to hypertrophic stimuli, HDAC4 is exported from the nucleus, freeing MEF2 to interact with histone acetyltransferases (HATs) and stimulate pro-hypertrophic gene expression.

Figure 3. A model for suppression of age-related HFpEF by HDAC inhibitors

Given the ability of HDAC inhibitors to block cardiac hypertrophy and fibrosis, as well as suppress oxidative stress and inflammation, it is hypothesized that these compounds will reduce age-depended cardiac dysfunction.