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This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.09-132415v1 23/11/3851    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Chandrasekaran, S. Articles by Menick, D. R. PubMed PubMed Citation Articles by Chandrasekaran, S. Articles by Menick, D. R.

Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes

Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

² Correspondence: Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty St., Box 250773, Charleston, SC 29425, USA. E-mail: menickd{at}musc.edu

It is becoming increasingly evident that histone deacetylases (HDACs) have a prominent role in the alteration of gene expression during the growth remodeling process of cardiac hypertrophy. HDACs are generally viewed as corepressors of gene expression. However, we demonstrate that class I and class II HDACs play an important role in the basal expression and up-regulation of the sodium calcium exchanger (Ncx1) gene in adult cardiomyocytes. Treatment with the HDAC inhibitor trichostatin A (TSA) prevented the pressure-overload-stimulated up-regulation of Ncx1 expression. Overexpression of HDAC5 resulted in the dose-dependent up-regulation of basal and -adrenergic stimulated Ncx1 expression. We show that Nkx2.5 recruits HDAC5 to the Ncx1 promoter, where HDAC5 complexes with HDAC1. Nkx2.5 also interacts with transcriptional activator p300, which is recruited to the Ncx1 promoter. We demonstrate that when Nkx2.5 is acetylated, it is found associated with HDAC5, whereas deacetylated Nkx2.5 is in complex with p300. Notably, TSA treatment prevents p300 from being recruited to the endogenous Ncx1 promoter, resulting in the repression of Ncx1 expression. We propose a novel model for Ncx1 regulation in which deacetylation of Nkx2.5 is required for the recruitment of p300 and results in up-regulation of exchanger expression.—Chandrasekaran, S., Peterson, R. E., Mani, S. K., Addy, B., Buchholz, A. L., Xu, L., Thiyagarajan, T., Kasiganesan, H., Kern, C. B., Menick, D. R. Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes.

Key Words: Nkx2.5 • acetylation • cardiac hypertrophy • p300 • transcriptional regulation

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