Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts.
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 kappaB (NF-kappaB) 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-kappaB, protein kinase CbetaII, 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(2+)-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-kappaB after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.
Kobayashi
Naohiko
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. nao-koba@dokkyomed.ac.jp
Yoshida
Kohtaro
K
Nakano
Shigefumi
S
Ohno
Tomoyuki
T
Honda
Takeaki
T
Tsubokou
Yusuke
Y
Matsuoka
Hiroaki
H
D000818:Animals; D002303:Cardiac Output, Low / Q000000981:diagnostic imaging / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D004452:Echocardiography; D004548:Elasticity; D000077545:Eplerenone; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013599:Systole; D020257:Ventricular Remodeling / Q000187:drug effects*
D002316:Cardiotonic Agents; D000451:Mineralocorticoid Receptor Antagonists; D016328:NF-kappa B; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E; D013481:Superoxides; D013148:Spironolactone; D000077545:Eplerenone; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases