Synergy of aldosterone and high salt induces vascular smooth muscle hypertrophy through up-regulation of NOX1.
Aldosterone and excessive salt intake are obviously implicated in human arteriosclerosis. Aldosterone activates NADPH oxidase that induces superoxide production and cardiovascular cell hypertrophy. The activity of NADPH oxidase is influenced by the expression of its subunit, through which, vasoactive agents activate in the enzyme. Here, we show that aldosterone elicited overexpression of the NOX1 catalytic subunit of NADPH oxidase in the presence of high salt in A7r5 vascular smooth muscle cells. We also showed that NOX1 is a key subunit involved in physiological aldosterone-induced NADPH oxidase activation. Aldosterone dose-dependently increased NOX1 expression and NADPH activity, which subsequently caused superoxide over-production and A7r5 cell hypertrophy. However, aldosterone had little effect on any of NOX1, superoxide over-production and cell hypertrophy in NOX1 knock-down A7r5 cells. These results suggest that the aldosterone-induced effects are mainly generated through NOX1. Aldosterone-induced NOX1 over-expression was augmented by 145 mM sodium chloride, as compared with control medium containing 135 mM NaCl. However, NOX1 over-expression was not induced in the absence of aldosterone, even in the presence of 185 mM NaCl. The mineralocorticoid receptor antagonist, eplerenone, completely abolished NOX1 over-expression, indicating that aldosterone is essential for this process.
Third Department of Internal Medicine, 23-3 Matsuoka-Shimoaitsuki, Eiheiji, Fukui 910-1193, Japan.
Chunyuan
C
Fan
Yasuyuki
Y
Kawai
Satoru
S
Inaba
Kenichiro
K
Arakawa
Masato
M
Katsuyama
Kouji
K
Kajinami
Toshihiro
T
Yasuda
Chihiro
C
Yabe-Nishimura
Tadashi
T
Konoshita
Isamu
I
Miyamori
D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017673:Sodium Chloride, Dietary / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D013481:Superoxides; D000450:Aldosterone; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat