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Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Fraccarollo, Daniela Berger, Stefan Galuppo, Paolo Kneitz, Susanne Hein, Lutz Schuetz, Guenther H. Frantz, Stefan Ertl, Georg Bauersachs, Johann |
| Copyright Year | 2011 |
| Abstract | 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 (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. METHODS AND RESULTS Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) 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 MR(MLCCre) mice. Chronically infarcted MR(MLCCre) 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)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) 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-κB 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. |
| Starting Page | 463 |
| Ending Page | 467 |
| Page Count | 5 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://circ.ahajournals.org/content/circulationaha/123/4/400.full.pdf |
| Alternate Webpage(s) | http://circ.ahajournals.org/content/circulationaha/early/2011/01/17/CIRCULATIONAHA.110.983023.full.pdf |
| Alternate Webpage(s) | http://circ.ahajournals.org/content/circulationaha/123/4/400.full.pdf?download=true |
| Alternate Webpage(s) | http://circ.ahajournals.org/content/circulationaha/early/2011/01/17/CIRCULATIONAHA.110.983023.full.pdf?download=true |
| PubMed reference number | 21242479v1 |
| Alternate Webpage(s) | https://doi.org/10.1161/CIRCULATIONAHA.110.983023 |
| DOI | 10.1161/circulationaha.110.983023 |
| Journal | Circulation |
| Volume Number | 123 |
| Issue Number | 4 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Cardiac Hypertrophy Echocardiography Heart failure Ligation Mineralocorticoid Receptor Mineralocorticoids Morbidity - disease rate Morphogenesis Myocardial Infarction Myocardium of left ventricle Myocytes, Cardiac NADPH Oxidase NOX4 gene Patients Pulmonary Edema Up-Regulation (Physiology) Ventricular Remodeling recombinase |
| Content Type | Text |
| Resource Type | Article |
