Published online before print November 5, 2009, doi: 10.1161/CIRCRESAHA.109.207084
Submitted on August 10, 2009
Revised on October 20, 2009
Accepted on October 22, 2009
Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control a Gender-Specific Pathway of Cardioprotection Mediated by the Estrogen Receptor
Eva van Rooij ;
From the Departments of Molecular Biology (E.v.R., J.F., L.B.S., E.N.O.), Cardiovascular and Thoracic Surgery (M.J.D.), Pathology (J.S.), and Internal Medicine (J.A.H.), University of Texas Southwestern Medical Center, Dallas; Department of Radiotherapy (V.L.T.), VU University Medical Center, Amsterdam, The Netherlands; and Department of Cardiology (H.J.C., L.J.D.W.), Maastricht University Medical Center, The Netherlands.
* To whom correspondence should be addressed. E-mail: eric.olson{at}utsouthwestern.edu.
Rationale: Gender differences in cardiovascular disease have long been recognized and attributed to beneficial cardiovascular actions of estrogen. Class II histone deacetylases (HDACs) act as key modulators of heart disease by repressing the activity of the myocyte enhancer factor (MEF)2 transcription factor, which promotes pathological cardiac remodeling in response to stress. Although it is proposed that HDACs additionally influence nuclear receptor signaling, the effect of class II HDACs on gender differences in cardiovascular disease remains unstudied.
Objective: We aimed to examine the effect of class II HDACs on post–myocardial infarction remodeling in male and female mice.
Methods and Results: Here we show that the absence of HDAC5 or -9 in female mice protects against maladaptive remodeling following myocardial infarction, which coincides with upregulation of estrogen-responsive genes in the heart. This genetic reprogramming coincides with a pronounced increase in expression of the estrogen receptor (ER)
gene, which we show to be a direct MEF2 target gene. ER also directly interacts with class II HDACs. Cardioprotection resulting from the absence of HDAC5 or -9 in female mice can be attributed, at least in part, to enhanced neoangiogenesis in the infarcted region via upregulation of the ER target gene vascular endothelial growth factor-a.
Conclusions: Our results reveal a novel gender-specific pathway of cardioprotection mediated by ER and its regulation by MEF2 and class II HDACs.
Key words: estrogen receptor • cardiac remodeling • myocardial infarction • class II HDACs