Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

Abstract

Abstract-Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor B (NF-B) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-B, protein kinase C␤II, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca 2ϩ -ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-B after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway. Key Words: aldosterone Ⅲ oxidative stress Ⅲ heart failure Ⅲ nitric oxide synthase Ⅲ signal transduction A ldosterone is implicated in the development of myocardial interstitial fibrosis and may play a critical role in the pathophysiology of heart failure, because there is evidence of an increased expression of the aldosterone synthase gene in the failing human heart, suggesting a role for locally produced aldosterone in the heart. 1 The pathophysiological role of aldosterone has received impressive support from 2 clinical studies, the Randomized ALdactone Evaluation Study (RALES) and the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS). 2,3 These studies showed that low doses of mineralocorticoid receptor (MR) antagonists led to a dramatic reduction of the mortality rate. However, little is known about the role of aldosterone in the development of cardiovascular remodeling and the progression to cardiac failure.The endothelium is an important modulator of vascular tone and function, in part by the synthesis and release of endothelial NO synthase (eNOS). Recently, some investigators 4,5 have sho...

Aldosterone and Metabolic Syndrome

“…2,3 This damage seems to be aldosterone mediated, and aldosterone blockade with mineralocorticoid receptor (MR) antagonists, such as spironolactone, may prevent the onset of these effects. 4,5 On the other hand, it cannot completely be ruled out that potassium and high blood pressure also play additional key roles in this damage. 6,7 This evidence has impressively been supported by clinical studies, such as the Randomized Aldactone Evaluation Study and the Eplerenone Post-Acute Myocardial Infarction Survival and Efficacy Study.…”

Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

“…MR is a metabolic nuclear receptor that plays a key role in the regulation of electrolyte homeostasis and blood pressure in the body [12] . MR activation mediates inflammation, proliferation and fibrosis [29,39,40] , while MR blockade exhibits beneficial effects on cardiovascular morbidity and mortality in patients with heart failure [41,42] . Recent studies have also shown that MR antagonists improve adipocyte dysfunction and insulin resistance in obese mice [31][32][33] .…”

Cardioprotective Effect of a Combination of Rho-Kinase Inhibitor and P38 MAPK Inhibitor on Cardiovascular Remodeling and Oxidative Stress in Dahl Rats

“…NAD(P)H oxidase p22 phox , p47 phox , gp91 phox , tumor necrosis factor-(TNF-), interleukin-1 (IL-1 ), monocyte chemoattractant protein-1 (MCP-1), procollagen type and , and fibronectin protein expressions were measured as described previously [18][19][20] . LV was homogenized (25% wt/vol) in 10 mmol/l HEPES buffer, pH 7.4, containing 320 mmol/l sucrose, 1 mmol/l EDTA, 1 mmol/l DTT, 10 g/ml leupeptin, and 2 g/ml aprotinin at 0 to 4 with a polytron homogenizer.…”

“…Histological detection of superoxide anion in the LV was performed using dihydroethidium (DHE) as described previously 18,19,21,23) .…”

“…Histologic examination was performed as described in detail previously 10,11,[18][19][20][21] . The wall-to-lumen ratio (the area of the vessel wall divided by the area of the total blood vessel lumen) was determined.…”