Mechanism of histone deacetylases in cardiac hypertrophy and its therapeutic inhibitors

Abstract

Cardiac hypertrophy is a key process in cardiac remodeling development, leading to ventricle enlargement and heart failure. Recently, studies show the complicated relation between cardiac hypertrophy and epigenetic modification. Post-translational modification of histone is an essential part of epigenetic modification, which is relevant to multiple cardiac diseases, especially in cardiac hypertrophy. There is a group of enzymes related in the balance of histone acetylation/deacetylation, which is defined as histone acetyltransferase (HAT) and histone deacetylase (HDAC). In this review, we introduce an important enzyme family HDAC, a key regulator in histone deacetylation. In cardiac hypertrophy HDAC I downregulates the anti-hypertrophy gene expression, including Kruppel-like factor 4 (Klf4) and inositol-5 phosphatase f (Inpp5f), and promote the development of cardiac hypertrophy. On the contrary, HDAC II binds to myocyte-specific enhancer factor 2 (MEF2), inhibit the assemble ability to HAT and protect against cardiac hypertrophy. Under adverse stimuli such as pressure overload and calcineurin stimulation, the HDAC II transfer to cytoplasm, and MEF2 can bind to nuclear factor of activated T cells (NFAT) or GATA binding protein 4 (GATA4), mediating inappropriate gene expression. HDAC III, also known as SIRTs, can interact not only to transcription factors, but also exist interaction mechanisms to other HDACs, such as HDAC IIa. We also present the latest progress of HDAC inhibitors (HDACi), as a potential treatment target in cardiac hypertrophy.

Keywords: cardiac hypertrophy; epigenetics; gene regulation; histone deacetylase; small molecule inhibitors.

FIGURE 1

Relationship of HAT and HDAC mediated histone acetylation/deacetylation leading to cardiac hypertrophy. As mentioned above, the Class IIa HDACs are not capable of deacetylating histone residues due to a within the catalytic domain mutation. Therefore, HDAC IIa represses gene transcription by binding with MEF2, recruiting other transcriptional repressors and epigenetic regulators to DNA promoter regions, and maintaining the acetylation level of histone (Figure 1 top part). Under adverse stimulation such as pressure overload, HDAC IIa isolate from MEF2 and transport to cytoplasm, while MEF2 recruiting HAT and catalyze histone lysine residue, and regulate transcription activity. Meanwhile, BET family recognize the acetylation of histone, and bind to related gene promoter region, and promote cardiac hypertrophy (Figure 1 left bottom part). Meanwhile, Class I and IIb HDACs catalyze the removal of acetyl groups from key lysine residues within histone. Histone deacetylation induces chromatin condensation, which represses gene transcription by making gene promoter and enhancer regions less accessible to transcription. Overexpression of HDAC I reduces acetylation of lysine in histone (such as H3K27ac), which will reduce anti-hypertrophy gene transcriptional activity, leading to cardiac hypertrophy. HDACi can inhibit HDAC I catalyze activity, and stop the transport of HDAC II from nuclear to cytoplasm, and protect the heart. MEF, myocyte-specific enhancer; HAT, histone acetyltransferase; HDAC, histone deacetyltransferase; HDACi, HDAC inhibitor. [By Figdraw (www.figdraw.com)].

FIGURE 2

A brief scheme of cardiac hypertrophy development and the key molecules mentioned in this review. Ang II, angiotensin II; Ca, calcium; CaMKII, calcium/calmodulin dependent protein kinase; Endo 1, Endothelin 1; GATA, GATA binding protein; HDAC, histone deacetylase; ISO, isoproterenol; MEF, myocyte-specific enhancer factor; NFAT, nuclear factor of activated T cells.