Cardioprotective mechanisms of spironolactone associated with the angiotensin-converting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats.
Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases (ERK) pathway, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase/lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway, and Rho-kinase pathway contribute to the pathogenesis of aldosterone/salt-induced hypertensive rats. Wistar rats were given 1% NaCl to drink and treated with one of the following combinations for 6 weeks: vehicle; aldosterone (0.75 microg/h); aldosterone plus a mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day); aldosterone plus an ACE inhibitor, imidapril (1 mg/kg/day); aldosterone plus an NAD(P)H oxidase inhibitor, apocynin (0.5 mmol/l); and aldosterone plus an Rho-kinase inhibitor, Y-27632 (3 mg/kg/day). Upregulated expression of ACE and EGFR and p44/p42ERK phosphorylation were suppressed by spironolactone or imidapril. Upregulated NAD(P)H oxidase subunits and LOX-1 expression were inhibited by spironolactone or apocynin. Increased expression of RhoA and Rho-kinase and myosin light chain phosphorylation were decreased by spironolactone or Y-27632. Moreover, these drugs effectively inhibited the vascular lesion formation, as measured by the medial thickness and level of perivascular fibrosis, and suppressed the expression of transforming growth factor-beta1, type I and III collagen, and monocyte chemoattractant protein-1 mRNA. Spironolactone may be useful as a cardioprotective agent to prevent cardiovascular remodeling via the ACE/EGFR/ERK, NAD(P)H oxidase/LOX-1, and Rho-kinase pathways.
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Shimotsuga-gun, Tochigi 321-0293, Japan.
Shigefumi
S
Nakano
Naohiko
N
Kobayashi
Kohtaro
K
Yoshida
Tomoyuki
T
Ohno
Hiroaki
H
Matsuoka
D000450:Aldosterone / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D024022:Fibrillar Collagens / Q000378:metabolism; D015870:Gene Expression; D006352:Heart Ventricles / Q000473:pathology*; D006973:Hypertension / Q000503:physiopathology*; D048289:Imidazolidines / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012965:Sodium Chloride; D013148:Spironolactone / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D018932:Chemokine CCL2; D024022:Fibrillar Collagens; D048289:Imidazolidines; D047908:Intracellular Signaling Peptides and Proteins; D000451:Mineralocorticoid Receptor Antagonists; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013148:Spironolactone; D012965:Sodium Chloride; D000450:Aldosterone; C065166:imidapril; D019255:NADPH Oxidases; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D007703:Peptidyl-Dipeptidase A; D020742:rhoA GTP-Binding Protein