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Role of HDACs in regulating Ncx1 expression in the heart
Author(s) -
Mani Santhosh Kumar,
Chandrasekaran Sangeetha,
Peterson Richard E,
Renaud Ludivine,
Buchholz Avery,
Addy Benjamin,
Xu Lin,
Kern Christine B,
Menick Donald R
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.209
Subject(s) - downregulation and upregulation , histone , activator (genetics) , gene expression , pressure overload , transcription factor , muscle hypertrophy , hdac4 , regulation of gene expression , microbiology and biotechnology , acetylation , diastole , medicine , endocrinology , biology , chemistry , gene , cardiac hypertrophy , blood pressure , genetics , histone deacetylase
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 Ca 2+ 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.