Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.
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.


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.


CONCLUSIONS
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.
Klinik fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Daniela
D
Fraccarollo
Stefan
S
Berger
Paolo
P
Galuppo
Susanne
S
Kneitz
Lutz
L
Hein
Günther
G
Schütz
Stefan
S
Frantz
Georg
G
Ertl
Johann
J
Bauersachs
D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D017353:Gene Deletion; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011654:Pulmonary Edema / Q000378:metabolism / Q000503:physiopathology; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*
D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018161:Receptors, Mineralocorticoid; D013481:Superoxides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse