The involvement of aldosterone in cyclic stretch-mediated activation of NADPH oxidase in vascular smooth muscle cells.
Increasing evidence suggests that aldosterone is implicated in the pathogenesis of cardiovascular diseases. We examined whether aldosterone contributes to the cyclic stretch (CS)-induced reactive oxygen species (ROS) generation in rat aortic smooth muscle cells (RASMCs). RASMCs were exposed to uniaxial CS and thereafter collected to evaluate the expressions of mRNA or protein relating aldosterone synthesis and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. CS strength-dependently enhanced NADPH oxidase activity. CS induced cytochrome P450 aldosterone synthase (CYP11B2) and increased aldosterone synthesis but did not influence the levels of 11beta-hydroxysteroid dehydrogenase 2 and mineralocorticoid receptor (MR). This CYP11B2 induction was almost completely suppressed by treatment with an extracellular signal-regulated kinase (ERK) inhibitor, U0126, whereas olmesartan, an angiotensin II (Ang II) receptor blocker (ARB), only partially suppressed CS-induced CYP11B2 expression and ERK phosphorylation. A selective MR antagonist, eplerenone (10 micromol l(-1)), significantly attenuated the CS-induced NADPH oxidase activation even in the presence of ARBs. In conclusion, aldosterone synthesis, which is partially independent of Ang II, may have an important role in CS-stimulated ROS generation in cultured RASMCs. We also suggest the potential benefit of eplerenone in the treatment of cardiovascular diseases.
Ohmine
Takahiro
T
Faculty of Medical Sciences, Department of Clinical Pharmacology, Kyushu University, Fukuoka 812-8582, Japan.
Miwa
Yoshikazu
Y
Takahashi-Yanaga
Fumi
F
Morimoto
Sachio
S
Maehara
Yoshihiko
Y
Sasaguri
Toshiyuki
T
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000235:genetics; D000450:Aldosterone / Q000097:blood / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000502:physiology*; D011311:Pressoreceptors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047228:Angiotensin II Type 1 Receptor Blockers; D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone; D009249:NADP; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D019405:Cytochrome P-450 CYP11B2; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases