Protein Acetylation in the Cardiorenal Axis

Abstract

Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-tomesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs. (Circ Res. 2010; 106:272-284.)Key Words: acetylation Ⅲ histone deacetylase Ⅲ heart failure Ⅲ kidney failure Ⅲ fibrosis I t has been estimated that more than 5 million adults in the United States experience heart failure, and more than 20 million adults show signs of chronic kidney disease (CKD). 1,2 Of the patients with heart failure, Ϸ50% experience heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure, which is characterized at the cellular level by myocyte hypertrophy and activation of extracellular matrix (ECM)-producing fibroblasts. Current standard of care for systolic heart failure (eg, ACE inhibitors and ␤-blockers) provide little to no benefit to patients with HFpEF. 3 Likewise, therapy for CKD primarily focuses on lowering blood pressure through modulation of the renin-angiotensin system and maintaining blood glucose control, and this strategy only minimally slows the glomerular injury and insidious fibrotic mechanisms that culminate in end-stage renal disease. 4 The high rate of morbidity and mortality in patients with HFpEF and CKD underscores the urgent need for novel therapeutics. Histone deacetylases (HDACs) are emerging as key players in the pathogenesis of these diseases, suggesting unexpected potential for pharmacological inhibitors of HDACs in the treatment of disorders of the cardiorenal axis.Histone acetyltransferases (HATs) and HDACs act in an opposing manner to control the acetylation state of proteins. The most well characterized role for protein acetylation is in Original received September 15, 2009; revision received October 6, 2009; accepted October 27, 2009 the control of gene transcription. Acetylation of the -amino groups of lysine residues in nucleosomal histone tails by HATs is thought to relax chromatin structure by weakening the interaction of the positively charged histone tails with the negatively charged phosphate backbone of DNA, allowing access of transcriptional activators and gene induction. Deacetylation of histones by HDACs alters the electrostatic properties of chromatin in a manner that favors gene repression. Interestingly, a recent genome-wide chromatin immunoprecipitation analysis revealed preferen...

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