Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of alpha-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility.
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: alpha-myosin heavy chain (MHC) expression and microtubular composition and organization. TSA upregulated the expression of alpha-MHC in cultured cardiac myocytes, as well as in an in vivo model of hypothyroid rats. Studies designed to delineate mechanisms of alpha-MHC induction by TSA revealed an obligatory role of early growth response factor-1 on activation of the alpha-MHC promoter. Concurrently, TSA downregulated the expression of alpha- and beta-tubulins and prevented the induction of tubulins by a hypertrophy agonist, ANG II. The ANG II-mediated increased proportion of alpha- and beta-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 alpha-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.
Davis
Francesca J
FJ
Department of Surgery, University of Chicago, IL 60637, USA.
Pillai
Jyothish B
JB
Gupta
Madhu
M
Gupta
Mahesh P
MP
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014404:Tubulin / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017874:Immediate-Early Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D014404:Tubulin; C012589:trichostatin A; D018995:Myosin Heavy Chains