Congestive heart failure is a complex disorder in which the heart is unable to pump a sufficient quantity of blood to meet the metabolic needs of the individual. It is the leading cause of death in the Western world with approximately 5,000,000 people (2-3% of the population) affected with this disease in the United States. Heart failure is a progressive disorder with a very poor prognosis. The factors that contribute to heart failure and drive its progress are the focus of our research program. At the molecular level, hypertrophic signals mediate change in transcriptional activation causing a change in gene expression. This programmatic change in gene expression negatively impacts calcium handling, contractile function, and metabolism. The Na+-Ca2+ exchanger (Ncx1) is one of the genes whose change in expression directly impacts cardiac function and physiology. Upregulation of Ncx1 directly results in depressed SR Ca2+ stores, impaired systolic function, and a greater potential for delayed after depolarizations (DADs), with subsequent ventricular tachycardia. Inhibition of exchanger activity or suppression of exchanger upregulation is expected to limit arrhythmias and potentially improve contractile function. In recent years, studies have shown that acetylation and deacetylation of cystolic and nuclear proteins play an important regulatory role in mediating the rapid and long-term changes in gene expression in response to pathophysiological stimuli and that acetylation imbalance can play an important role in cardiovascular disease. In this application, we will examine the role that histone deacetylases (HDAC) have in the regulation of Ncx1. Our findings reveal a unique role for HDAC1/2/5 as required for transcriptional activation of Ncx1 in the adult heart and provide a possible molecular explanation for the cardioprotective actions of HDAC inhibitors. The preliminary data support our hypothesis that the HDAC1/2/5 complex deacetylates Nkx2.5 leading to the recruitment of p300 and upregulation of the Ncx1 promoter. Experiments in Aim 1 will identify the acetylated residues and test how acetylation affects Nkx2.5 interaction with p300 and Ncx1 expression.
In Aim 2 we will use ChIP and re-ChIP to test our hypothesis by examining the chronological sequence of events that occur during Ncx1 transcriptional upregulation and in Aim 3 investigate the clinical relevance and requirement of HDAC5/9 in vivo. Our long-term objectives are to provide insight into the diverse mechanisms by which HDACs regulate cardiac gene expression and improve our overall understanding regarding how the acetylation state of nuclear factors affect transcription. This work will contribute to our understanding of the role HDACs play in the regulation of cellular events and gene expression in physiology and pathophysiology of the heart. These studies will have the potential of demonstrating the therapeutic potential of HDAC inhibitors in preserving systolic function in cardiac hypertrophy.

Public Health Relevance

Congestive heart failure is the leading cause of death in the United States. Calcium, which is critical for heart contraction is mis-regulated in the failing heart. We have found that one of the proteins regulating cardiac calcium is upregulation in cardiac hypertrophy and failure. We have found that a regulator of gene expression prevents the upregulation of the exchanger in a hypertrophic heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095696-04
Application #
8241023
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2009-04-20
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$365,063
Indirect Cost
$117,563
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Aune, Sverre E; Herr, Daniel J; Mani, Santhosh K et al. (2014) Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion. J Mol Cell Cardiol 72:138-45
Menick, Donald R; Li, Mona S; Chernysh, Olga et al. (2013) Transcriptional pathways and potential therapeutic targets in the regulation of Ncx1 expression in cardiac hypertrophy and failure. Adv Exp Med Biol 961:125-35
Kern, Christine B; Wessels, Andy; McGarity, Jessica et al. (2010) Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies. Matrix Biol 29:304-16
Crosson, Craig E; Mani, Santhosh K; Husain, Shahid et al. (2010) Inhibition of histone deacetylase protects the retina from ischemic injury. Invest Ophthalmol Vis Sci 51:3639-45