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-myosin heavy chain and tubulins: Implication for gain in cardiac muscle contractility
1 Department of Surgery (Division of Cardiothoracic Surgery), University of Chicago, Chicago, IL, USA
2 The Heart Institute of Children, Hope Children Hospital and Department of Physiology and Biophysics, University of Illinois at Chicago, Oak Lawn, IL, USA
3 Department of Surgery (Division of Cardiothoracic Surgery), University of Chicago, Chicago, IL, USA; Committee on Molecular Medicine, University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: mgupta{at}surgery.bsd.uchicago.edu.
Histone deaceteylases (HDACs) are a family of enzymes that catalyze removal of acetyl groups from core histones, resulting in change of chromatin structure and the gene transcription activity. In the heart HDACs have been shown to be targets of hypertrophic signaling and their non-specific inhibition by Trichostatin-A (TSA) attenuated hypertrophy of cultured cardiac myocytes. In this study we examined the effect of TSA on two major determinants of cardiac contractility: 
-MHC expression and micro-tubular composition/organization. TSA up-regulated the expression of -MHC in cultured cardiac myocytes, as well as in an invivo model of hypothyroid rats. Studies designed to delineate mechanisms of -MHC induction by TSA revealed an obligatory role of EGR-1 on activation of the -MHC promoter. Concurrently, TSA down regulated the expression of - and 
-tubulins, and prevented the induction of tubulins by a hypertrophy agonist, angiotensin-II (Ang-II). Ang-II mediated increased proportion of - and -tubulins associated with polymerized microtubules was also markedly reduced following treatment of cells by TSA. Results obtained from immunoflorescent microscopy indicated that TSA had no noticeable effect on the organization of cardiac microtubules in control cells; whereas, it prevented the Ang-II-induced dense parallel linear arrays of microtubules, to a profile similar to those of controls. Together these results demonstrate that inhibition of HDACs by TSA regulates the cardiac -MHC and tubulins in a manner, predictive of improved cardiac contractile function. These studies improve our understanding of the role of HDACs on cardiac hypertrophy, with implications in development of new therapeutic agents for treatment of cardiac abnormalities.
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