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Abstract
BackgroundInterstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure. Recent studies showed that histone deacetylase (HDAC) inhibitors retard fibrosis formation in acute MI settings. However, it is unknown whether HDAC inhibition can reverse cardiac fibrosis in ischemic heart failure. In addition, specific HDAC isoforms involved in cardiac fibrosis and myofibroblast activation are not well defined. Thus, the purpose of this study is to determine the effects of selective class I HDAC inhibition on cardiac fibroblasts activation and cardiac fibrosis in a congestive heart failure (CHF) model secondary to MI.MethodsMI was created by left anterior descending (LAD) coronary artery occlusion. Class I HDACs were selectively inhibited via Mocetinostat in CD90+ fibroblasts isolated from atrial and ventricular heart tissue in vitro. In vivo, Class I HDACs were inhibited in 3 weeks post MI rats by injecting Mocetinostat for the duration of 3 weeks. Cardiac function and heart tissue were analyzed at 6 weeks post MI.ResultsIn sham hearts, HDAC1 and HDAC2 displayed differential expression patterns where HDAC1 mainly expressed in cardiac fibroblast and HDAC2 in cardiomyocytes. On the other hand, we showed that HDAC1 and 2 were upregulated in CHF hearts, and were found to co-localize with CD90+ cardiac fibroblasts. In vivo treatment of CHF animals with Mocetinostat improved left ventricle end diastolic pressure and dp/dt max and decreased the total collagen amount. In vitro treatment of CD90+ cells with Mocetinostat reversed myofibroblast phenotype as indicated by a decrease in α-Smooth muscle actin (α-SMA), Collagen III, and Matrix metalloproteinase-2 (MMP2). Furthermore, Mocetinostat increased E-cadherin, induced β-catenin localization to the membrane, and reduced Akt/GSK3β signaling in atrial cardiac fibroblasts. In addition, Mocetinostat treatment of atrial CD90+ cells upregulated cleaved-Caspase3 and activated the p53/p21 axis.ConclusionsTaken together, our results demonstrate upregulation of HDAC1 and 2 in CHF. In addition, HDAC inhibition reverses interstitial fibrosis in CHF. Possible anti-fibrotic actions of HDAC inhibition include reversal of myofibroblast activation and induction of cell cycle arrest/apoptosis.
Highlights
Interstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure
HDAC1 and 2 levels are elevated in congestive heart failure (CHF) First, we investigated the time course of histone deacetylase (HDAC) 1 and 2 protein levels using western blot analysis at three time points following MI: at 3 days (Acute MI-AMI), 3 weeks (3w CHF) where the scar was formed and animals progressed into heart failure, and 6 weeks (6w CHF) where animals were in de-compensated heart failure [14] that is in junction with development of prominent fibrosis in the ventricles and atria
At 3 weeks and 6 weeks after MI, HDAC1 and HDAC2 levels were upregulated in the infarcted Left ventricle (LV) (Figure 1B and C)
Summary
Interstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure. Recent studies showed that histone deacetylase (HDAC) inhibitors retard fibrosis formation in acute MI settings It is unknown whether HDAC inhibition can reverse cardiac fibrosis in ischemic heart failure. Small molecule HDAC inhibitors, especially Class I and II inhibitors, were shown to effectively retard myocardial remodeling, decrease interstitial fibrosis, and improve cardiac function in pathological heart conditions [9,10,11,12,13]. In most of these studies, HDAC inhibitors were applied in acute MI settings rather than after development of interstitial fibrosis in CHF. We explore the anti-fibrotic mechanisms of Mocetinostat, a highly specific HDAC1, 2, and 3 inhibitor, in cardiac fibroblasts
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