Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

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. ) 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 ⅐Ϫ 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-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.) Methods and Results-ControlKey Words: acute myocardial infarction Ⅲ aldosterone Ⅲ heart failure Ⅲ mineralocorticoid receptor Ⅲ remodeling M ineralocorticoid receptor (MR) blockade reduces morbidity and mortality in patients with heart failure. 1-4 However, it remains unclear whether the cardioprotective effects of MR antagonists can be attributed to inhibition of the cardiomyocyte MR. While attenuation of left ventricular (LV) dilation and excessive extracellular matrix turnover 5-9 and prevention of electric remodeling appear to be essential mechanisms of MR antagonism, 10,11 extracardiac effects such as renal sodium excretion and potassium sparing, restoration of autonomic balance, and improvement in vascular endothelial dysfunction may be of particular importance. 9,[12][13][14] Clinical Perspective on p 408To investigate the pathophysiological role of the cardiomyocyte MR in ischemic heart failure, we investigated cardiac remodeling after myocardial infarction (MI) in mice with cardiac myocyte-specific inactivation of the MR gene. LV rem...

Mineralocorticoid Receptor, the Main Player in Aldosterone-Induced Large Artery Stiffness

“…8 Specific deletion of MR in cardiomyocytes improved infarct healing and adverse remodeling after myocardial infarction. 9 In the present issue of Hypertension, Galmiche et al 10 have demonstrated the major implication of MR in large artery remodeling in response to aldosterone. These investigators tested the effect of uninephrectomy associated with aldosterone .…”

Galectin-3 in acute coronary syndrome

“…Similarly, van der Velde found that high baseline Gal-3 levels to be associated with a lower LVEF and a larger infarct size in acute STEMI patients underwent pPCI at 4 months follow-up [46]. Also Mayr et al investigated the correlation between Gal-3 with infarct size and LVEF in reperfused STEMI patients after 4 months [57]. They failed to find a correlation between Gal-3 and LVEF, but documented a significant correlation between Gal-3 and infarct size (r:0.406, P: 0.036).…”

“…The current American and European guidelines recommend a mineralocorticoid receptor antagonist (MRA) for treatment of AMI patients with LV dysfunction (≤ 40%) and HF symptoms [55,56]. Indeed, MRAs (eplerenone and spironolactone) have a cardioprotective effect reducing post-infarction collagen synthesis and progressive cardiac remodeling [57,58]. In an experimental model of left ventricular systolic dysfunction after AMI, Lax et al have shown MRAs down-regulated Gal-3 expression in the myocardium after AMI and such regulation correlated with lower expression levels of fibrosis and inflammatory markers including collagen type I, collagen III and TNF-α [59].…”

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

“…These results have prompted further studies of the role of MR in cardiovascular tissues, including cardiomyocytes, smooth muscle cells, endothelia, and macrophages, to understand the cell‐specific contribution of MR to BP and cardiovascular diseases, using tissue‐specific MR knockout mouse models. The deletion of cardiomyocyte MR prevents cardiac remodeling after myocardial infarction13 and cardiac fibrosis with deoxycorticosterone acetate (DOCA)/salt treatment 14. Endothelial MR is involved in inflammatory and profibrotic responses15 and the regulation of vasomotor function 16.…”