Aldosterone induces superoxide generation via Rac1 activation in endothelial cells.
Currently, aldosterone is believed to be involved in the development of cardiovascular injury as a potential cardiovascular risk hormone. However, its exact cellular mechanisms remain obscure. This study was undertaken to examine the effect of aldosterone on superoxide production in cultured rat aortic endothelial cells with possible involvement of the small GTP-binding (G) protein Rac1. The aldosterone levels showed a time-dependent (6-24 h) and dose-dependent (10(-8) to 10(-6) m) increase in superoxide generation, whose effect was abolished by mineralocorticoid receptor antagonist (eplerenone), Src inhibitor (PP2), and reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase inhibitor (apocynin). Aldosterone activated NADP(H) oxidase and Rac1, whose effects were abolished by eplerenone. The aldosterone-induced superoxide generation was abolished either by nonselective small G protein inhibitor (Clostridium difficile toxin A) or dominant-negative Rac1. Dominant-negative Rac1 also inhibited aldosterone-induced ACE gene expression. Thus, the present study is the first to demonstrate that aldosterone induces superoxide generation via mineralocorticoid receptor-mediated activation of NAD(P)H-oxidase and Rac1 in endothelial cells, thereby contributing to the development of aldosterone-induced vascular injury.
Iwashima
Fumiko
F
Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8513, Japan.
Yoshimoto
Takanobu
T
Minami
Isao
I
Sakurada
Maya
M
Hirono
Yuki
Y
Hirata
Yukio
Y
D000098:Acetophenones / Q000494:pharmacology; D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077545:Eplerenone; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000098:Acetophenones; D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013481:Superoxides; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; C056165:acetovanillone; D019255:NADPH Oxidases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein