Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

Abstract

Background-Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results-We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4Ϯ0.1 versus 3.7Ϯ0.1 mm) and end-systolic (2.0Ϯ0.1 versus 2.5Ϯ0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42Ϯ2% versus 34Ϯ4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions-Mineralocorticoid

Aldosterone activates endothelial exocytosis

“…Our findings support the studies of others showing that MR mediates vascular inflammation. For example, the MR antagonists decrease oxidative stress and vascular inflammation in animal models (17)(18)(19)(20)(21)44).…”

“…Aldosterone infusion induces leukocyte infiltration into arteries of rats and increases the expression of proinflammatory markers (15,16). Mineralocorticoid receptor (MR) antagonists decrease monocyte infiltration into the vascular wall in hypertensive rats, in rats treated with aldosterone, and in hypertensive mice (17)(18)(19)(20)(21). Clinical studies also show that aldosterone increases markers of vascular inflammation.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…Mechanical stress due to pressure overload activates the renin-angiotensin-aldosterone system (RAAS), triggering inflammatory signaling and leading to downstream stimulation of TGF-β cascades. Neurohumoral mediators, cytokines, and growth factors directly stimulate a fibrogenic program, triggering myofibroblast conversion and stimulating synthesis of large amounts of structural matrix proteins (103)(104)(105)(106). Stress-induced fibroblast activation in the pressure-overloaded myocardium may also be indirect, at least in part, requiring stimulation of fibrogenic cascades in cardiomyocytes and immune cells.…”

Role of mineralocorticoid receptor on atrial structural remodeling and inducibility of atrial fibrillation in hypertensive rats

“…7,8 Recent large clinical trials, both the Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) studies, and other animal studies have demonstrated the beneficial effects of mineralocorticoid receptor (MR) antagonists on the prognosis and ventricular remodeling. [9][10][11][12] However, little is known about the effects of the MR antagonist on atrial remodeling in hypertension. MR stimulation is linked to interstitial fibrosis, inflammation, hypertrophy and superoxide production in the heart, [13][14][15] all of which are known to provide a pathogenic substrate for AF.…”