Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

TLDR

Mineralocorticoid receptor blockade improves heart‑failure outcomes, but the mechanisms remain unclear. The study examined whether cardiomyocyte‑specific deletion of the MR gene mitigates left‑ventricular remodeling after myocardial infarction in mice. Using a conditional MR knockout driven by the myosin light‑chain promoter, mice underwent coronary artery ligation, and the absence of MR accelerated stress‑induced NF‑κB activation, reduced apoptosis, and altered oxidative signaling. MR deletion prevented baseline cardiac changes, attenuated LV dilation and dysfunction, reduced pulmonary edema, hypertrophy, extracellular matrix deposition, and oxidative stress, while enhancing neovessel formation and collagen organization, ultimately improving infarct healing and limiting adverse remodeling.

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.