(The FASEB Journal. 2008;22:lb209)
© 2008 FASEB
Role of HDACs in regulating Ncx1 expression in the heart
Santhosh Kumar Mani,
Sangeetha Chandrasekaran,
Richard E Peterson,
Ludivine Renaud,
Avery Buchholz,
Benjamin Addy,
Lin Xu,
Christine B Kern and
Donald R Menick
Medicine, Cardiology, Medical University Of South Carolina, Charleston, SC
ABSTRACT
When hemodynamic load is too great for hypertrophic growth to normalize, cardiovascular function deteriorates resulting in a reduction of ejection fraction and systolic and diastolic ventricular dysfunction. At the molecular level, there is transcriptional activation of a set of genes in response to hypertrophic remodeling. Sodium calcium exchanger 1 (Ncx1) is one of the genes whose expression changes during hypertrophy and has been shown to directly impact cardiac function. Upregulation of Ncx1 directly results in depressed SR Ca2+ stores, impaired systolic function, and a greater potential for delayed after depolarizations. Protein acetylation regulated by histone acetyl transferaces (HATs) and histone deacetylases (HDACs) has been shown to play a significant role in the regulation of gene expression. Our novel findings demonstrate that inhibition of class I and II HDACs prevents pressure-overload induced upregulation of Ncx1 in a murine model of cardiac hypertrophy. Our results reveal an unexpected role for HDAC5 as a transcriptional co-activator of Ncx1 expression and we further demonstrate that this activation is mediated via interaction with transcription factor Nkx2.5. Thus, our findings clearly highlight another layer of the complex role that HDACs play in the regulation of cellular events and gene expression in physiology and pathophysiology of the heart. Supported by NIH HL066223 and HL48788.
