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Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

Circulation (New York, N.Y.), 2011-02, Vol.123 (4), p.400-408 [Peer Reviewed Journal]

2015 INIST-CNRS ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/circulationaha.110.983023 ;PMID: 21242479 ;CODEN: CIRCAZ

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Title:
Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction
Author: FRACCAROLLO, Daniela ; BERGER, Stefan ; GALUPPO, Paolo ; KNEITZ, Susanne ; HEIN, Lutz ; SCHÜTZ, Günther ; FRANTZ, Stefan ; ERTL, Georg ; BAUERSACHS, Johann
Subjects: Animals ; Apoptosis ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cardiomegaly - metabolism ; Cardiomegaly - physiopathology ; Cells, Cultured ; Coronary heart disease ; Coronary Vessels - metabolism ; Coronary Vessels - physiopathology ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Female ; Gene Deletion ; Heart ; Male ; Medical sciences ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Transgenic ; Myocardial Infarction - genetics ; Myocardial Infarction - metabolism ; Myocardial Infarction - physiopathology ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - physiology ; NADPH Oxidase 2 ; NADPH Oxidase 4 ; NADPH Oxidases - metabolism ; Neovascularization, Physiologic ; NF-kappa B - metabolism ; Pulmonary Edema - metabolism ; Pulmonary Edema - physiopathology ; Receptors, Mineralocorticoid - genetics ; Receptors, Mineralocorticoid - metabolism ; Receptors, Mineralocorticoid - physiology ; Superoxides - metabolism ; Up-Regulation ; Ventricular Remodeling - genetics ; Ventricular Remodeling - physiology
Is Part Of: Circulation (New York, N.Y.), 2011-02, Vol.123 (4), p.400-408
Description: 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. 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. 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.
Publisher: Hagerstown, MD: Lippincott Williams & Wilkins
Language: English
Identifier: ISSN: 0009-7322
EISSN: 1524-4539
DOI: 10.1161/circulationaha.110.983023
PMID: 21242479
CODEN: CIRCAZ
Source: GFMER Free Medical Journals
MEDLINE

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Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

2015 INIST-CNRS ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/circulationaha.110.983023 ;PMID: 21242479 ;CODEN: CIRCAZ

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