Abstract 15605: Downregulation Of Methyl-CpG Binding Protein 2 Attenuates Cardiac Remodeling After Chronic Pressure Overload In Mice
Introduction: Epigenetic processes involving DNA methylation and its recognition by specific binding proteins play an important role in cell differentiation, growth and proliferation. However, the significance of these mechanisms in the heart is largely unknown. Thus, the aims of this project were (1) to study the expression of methyl-CpG binding protein 2 (MeCP2) in human and murine heart failure and (2) to assess the functional relevance of MeCP2 in transgenic mouse models with cardiac-myocyte specific MeCP2 expression.
Methods and Results: In ventricular biopsies from failing human hearts and in mouse hearts after 8 weeks of transverse aortic constriction (TAC), MeCP2 mRNA expression was significantly downregulated to 8 ± 5% of the expression level in healthy murine hearts (p<0.01). Transgenic mice overexpressing MeCP2 under the cardiac α-myosin heavy chain gene (αMHC) promoter were generated by pronuclear injection. All transgenic MeCP2 founder mice were lost within 8 weeks after birth (p<0.01 vs. non-transgenic mice, n=6, Kaplan-Meier analysis) due to rapidly developing cardiomyopathy with severe interstitial fibrosis. In order to prevent the decrease in MeCP2 expression after TAC, mice with conditional cardiac myocyte-specific expression of MeCP2 were generated using the tetracycline system (dTg-MeCP2). Transgene induction for up to 10 weeks did not affect cardiac myocyte size or interstitial matrix deposition. After TAC, total MeCP2 mRNA levels were not significantly different in dTg-MeCP2 mice compared with unoperated control mice. Prevention of MeCP2 downregulation in dTg-MeCP2 mice after TAC resulted in reduced left ventricular contractility (dTg-MeCP2 5048 ± 264 mmHg/s vs. control 5726 ± 145 mmHg/s; p<0.05), greater cardiac hypertrophy (ventricle/body weight ratio: dTg-MeCP2 10.3 ± 0.5 vs. control 8.2 ± 0.5, n=9 per group; p<0.001), increased cardiac myocyte size (myocyte cross section: dTg-MeCP2 118 ± 2% of control TAC; p<0.05) and increased interstitial fibrosis (fibrosis area: dTg-MeCP2 10.5 ± 1.1% vs. control 4.4 ± 1.3%; p<0.01).
Conclusion: Downregulation of MeCP2 expression during cardiac hypertrophy and failure may be protective to attenuate cardiac remodeling and left ventricular dysfunction.
- © 2010 by American Heart Association, Inc.