Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes.
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 alpha-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
Sangeetha
S
Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Peterson
Richard E
RE
Mani
Santhosh K
SK
Addy
Benjamin
B
Buchholz
Avery L
AL
Xu
Lin
L
Thiyagarajan
Thirumagal
T
Kasiganesan
Harinath
H
Kern
Christine B
CB
Menick
Donald R
DR
D000818:Animals; D002415:Cats; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; C484469:Nkx2-5 protein, mouse; D019831:Sodium-Calcium Exchanger; D014157:Transcription Factors; C110374:sodium-calcium exchanger 1; C012589:trichostatin A; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C484389:Hdac1 protein, mouse; C498618:Hdac5 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases