Abstract
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.
Highlights
Aldosterone activated NADP(H) oxidase and Rac1, whose effects were abolished by eplerenone
Because it has been shown that aldosterone activates NAD(P)H oxidase via Src in cultured rat vascular smooth muscle cells (VSMCs) [27], we tested the effect of PP2, a selective Src inhibitor, on aldosterone-induced superoxide generation
The present study demonstrated for the first time that aldosterone induces superoxide generation via NAD(P)H oxidase and Rac1 activation through mineralocorticoid receptor (MR) in rat aortic endothelial cells (RAECs)
Summary
Aldosterone activated NADP(H) oxidase and Rac, whose effects were abolished by eplerenone. The present study is the first to demonstrate that aldosterone induces superoxide generation via mineralocorticoid receptormediated activation of NAD(P)H-oxidase and Rac in endothelial cells, thereby contributing to the development of aldosterone-induced vascular injury. Aldosterone has recently been shown to increase superoxide production and induces cardiovascular injury in mineralocorticoid-induced hypertensive animals, whose effects were blocked by the administration of subpressor doses of MR antagonists as well as antioxidants and/or NAD(P)H oxidase inhibitors (3, 10 –13). These experimental results suggest that oxidative stress induced by NAD(P)H oxidase plays an important role in the development of aldosterone-induced cardiovascular injury. The molecular mechanism underlying vascular superoxide generation and NAD(P)H oxidase activation by aldosterone remains unknown
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