Oxidative stress induces vascular heme oxygenase-1 expression in ovariectomized rats.
Heme oxygenase-1 (HO-1), an inducible stress protein, has been implicated in cytoprotection against oxidative stress in vitro and in vivo. Estrogens also have antioxidant effects. This study investigated the time course of HO-1 and inducible nitric oxide synthase (iNOS) expression in the aortas of ovariectomized rats, and the regulatory relationship between the NO/NOS and the carbon monoxide/HO systems. HO-1 and iNOS protein expression was induced by ovariectomy (Ovx) and was extremely high 2-6 weeks after Ovx compared with the sham-operated group. Expression of the constitutive enzymes HO-2 and endothelial NOS did not differ significantly between sham-operated and Ovx rats. 17beta-Estradiol (E(2)) replacement reversed these changes in rats after Ovx. Long-term treatment with the antioxidant tempol significantly inhibited HO-1 and iNOS expression. The iNOS inhibitor aminoguanidine significantly suppressed the induction of HO-1. Oxidized glutathione in the hearts of Ovx rats increased gradually, with significant elevation at 3-6 weeks after Ovx compared with the sham-operated group, whereas plasma levels of NO metabolites were significantly reduced 4-6 weeks after Ovx. Treatment with the HO inhibitor zinc protoporphyrin IX blocked HO-1 induction, but significantly increased the plasma levels of NO metabolites. In conclusion, HO-1 is induced by oxidative stress resulting from E(2) depletion. The NO/iNOS system contributes to the induction of HO-1, which may subsequently suppress iNOS activity to modulate vasculoprotective effects after menopause.
Lee
Yen-Mei
YM
Department of Pharmacology, National Defense Medical Center, Nei-Hu, Taipei, Taiwan. ymlee@mail.ndmctsgh.edu.tw
Cheng
Pao-Yun
PY
Hong
Su-Fen
SF
Chen
Shu-Ying
SY
Lam
Kwok-Keung
KK
Sheu
Joen-Rong
JR
Yen
Mao-Hsiung
MH
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology*; D001835:Body Weight; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004790:Enzyme Induction; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D005260:Female; D019803:Glutathione Disulfide / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing); D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D009929:Organ Size; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D013113:Spin Labels; D013997:Time Factors; D014599:Uterus / Q000033:anatomy & histology
D003497:Cyclic N-Oxides; D006146:Guanidines; D006360:Heat-Shock Proteins; D009566:Nitrates; D009573:Nitrites; D011524:Protoporphyrins; D013113:Spin Labels; C017803:zinc protoporphyrin; D004958:Estradiol; D010105:Oxygenases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C004479:pimagedine; C001803:tempol; D019803:Glutathione Disulfide