HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/H1477    most recent 00789.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Davis, F. J. Articles by Gupta, M. P. Search for Related Content PubMed PubMed Citation Articles by Davis, F. J. Articles by Gupta, M. P.

Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of -MHC and cardiac tubulins: implication for gain in cardiac muscle contractility

¹Department of Surgery (Division of Cardiothoracic Surgery) and ³Committee on Molecular Medicine, University of Chicago, Chicago; ²The Heart Institute of Children, Hope Childrens Hospital, Oak Lawn, and Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois

Submitted 4 August 2004 ; accepted in final form 15 September 2004

Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from core histones, resulting in change of chromatin structure and gene transcription activity. In the heart, HDACs are targets of hypertrophic signaling, and their nonspecific inhibition by trichostatin A (TSA) attenuates hypertrophy of cultured cardiac myocytes. In this study, we examined the effect of TSA on two major determinants of cardiac contractility: -myosin heavy chain (MHC) expression and microtubular composition and organization. TSA upregulated the expression of -MHC in cultured cardiac myocytes, as well as in an in vivo model of hypothyroid rats. Studies designed to delineate mechanisms of -MHC induction by TSA revealed an obligatory role of early growth response factor-1 on activation of the -MHC promoter. Concurrently, TSA downregulated the expression of - and -tubulins and prevented the induction of tubulins by a hypertrophy agonist, ANG II. The ANG II-mediated increased proportion of - and -tubulins associated with polymerized microtubules was also markedly reduced after treatment of cells by TSA. Results obtained from immunofluorescent 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 that 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.

histone deacetylase inhibitors; myosin heavy chain; hypertrophy; heart failure

This article has been cited by other articles:

				G. W. Moseley, X. Lahaye, D. M. Roth, S. Oksayan, R. P. Filmer, C. L. Rowe, D. Blondel, and D. A. Jans Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response J. Cell Sci., October 15, 2009; 122(20): 3652 - 3662. [Abstract] [Full Text] [PDF]

				G. Cooper IV Proliferating cardiac microtubules Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H510 - H511. [Full Text] [PDF]

				J. B. Pillai, M. Chen, S. B. Rajamohan, S. Samant, V. B. Pillai, M. Gupta, and M. P. Gupta Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the {alpha}-myosin heavy chain expression Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1388 - H1397. [Abstract] [Full Text] [PDF]

				T.-M. Lee, M.-S. Lin, and N.-C. Chang Inhibition of histone deacetylase on ventricular remodeling in infarcted rats Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H968 - H977. [Abstract] [Full Text] [PDF]

				J. Backs and E. N. Olson Control of Cardiac Growth by Histone Acetylation/Deacetylation Circ. Res., January 6, 2006; 98(1): 15 - 24. [Abstract] [Full Text] [PDF]

				S. Danzi, P. Dubon, and I. Klein Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1506 - H1511. [Abstract] [Full Text] [PDF]