Journal
CIRCULATION
Volume 123, Issue 4, Pages 400-U354Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.110.983023
Keywords
acute myocardial infarction; aldosterone; heart failure; mineralocorticoid receptor; remodeling
Funding
- German Heart Failure Network [TP 8]
- European Union [LSHM-CT-2005-018652]
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Background-Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MRMLCCre) that were generated with a conditional MR allele (MRflox) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Methods and Results-Control (MRflox/flox, MRflox/wt) and MRMLCCre mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MRMLCCre mice. Chronically infarcted MRMLCCre mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O-2(center dot-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MRMLCCre mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-kappa B and reduced apoptosis early after myocardial infarction. Conclusion-Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression. (Circulation. 2011;123:400-408.)
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