The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

Abstract

Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure

“…These and other mechanisms involved in the epigenetic control of gene expression in cardiac hypertrophy and heart failure have also been very clearly presented in a recent review article to which we refer for further details ( 258 ). In fact, HDAC inhibitors have already been successfully tested in preclinical models of heart failure [recently reviewed in ( 259 )]. Histone deacetylases involved in the regulation of endothelial cell function include HDAC1, which has been shown to decrease basal and endothelin-1 stimulated NO production via eNOS protein deacetylation ( 260 ), whereas HDAC2 upregulates the release of NO by decreasing arginase-2 gene expression ( 261 , 262 ).…”

The role of post‐translational modifications in cardiac hypertrophy

“…Cells need to be connected to various PTM signals and coordinated with each other to properly regulate cardiac hypertrophy. Furthermore, emerging evidence has highlighted important roles for crosstalk between different pairs of PTMs, such as ubiquitylation‐phosphorylation, SUMOylation‐phosphorylation, acetylation‐phosphorylation, O‐linked glycosylation‐phosphorylation, and acetylation‐methylation . For example, TAK1, an important signal transmitter, transmits the upstream signal from the receptor complex to the downstream signalling molecules.…”

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

“…Apart from their desired anticancer activity, conventional tumor therapeutics also evoke numerous agent-specific adverse effects in normal tissue. Regarding possible long-term adverse effects of HDACi, their potency to harm genetic stability is of utmost concern [ 40 ], especially for possible indications in case of widespread non-malignant human diseases, such as cardiovascular [ 41 ], neurological [ 20 , 42 , 43 , 44 , 45 ], and immunological disorders [ 46 ]. Remarkably, these illnesses are currently emerging as promising novel areas of application of HDACi [ 47 , 48 , 49 ].…”