Heme oxygenase-1 in vascular smooth muscle cells counteracts cardiovascular damage induced by angiotensin II.
Heme oxygenase (HO) is a microsomal enzyme that catalyzes the degradation of heme into biliverdin, which is subsequently reduced to bilirubin, free iron and carbon monoxide (CO), and induction of heme oxygenase-1 (HO-1) is potentially associated with cellular protection, especially against oxidative insults. Using transgenic mice that overexpress HO-1 (HO-1 Tg) specifically in vascular smooth muscle cells, we investigated the organ-protective effects of HO-1 against angiotensin II (Ang II). Following administration of Ang II and a high- salt diet for 14 days, marked intimal hyperplasia as well as inflammatory changes were observed in coronary arteries of Ang II/salt-treated wild type (Wt) mice. In Wt mice, Ang II/salt loading increased urinary excretion of 8- hydroxydeoxyguanosine (8-OHdG) and 8-lso-Prostaglandin F2 alpha. Cardiac levels of MDA and 4-HAE, markers of lipid peroxidation, and GSSG/GSH were also increased in Wt. mice after Ang II/salt loading, but not in HO-1 Tg mice. Consistently, immunostaining for both 8-0HdG, a marker of oxidative DNA damage, and 3-nitrotyrosine, the metabolites of reactive oxygen species, were apparently increased in the Ang II/salt-treated heart of Wt. mice; however, no significant changes in these responses were detected in HO-1 Tg mice after Ang II/salt loading. These data suggest that increased oxidative stress might be involved in the coronary artery changes induced by Ang II/salt loading. The evidence presented in the current study indicates that vascular HO-1 exerts its protective effect against cardiovascular damage, possibly through the inhibition of oxidative stress.
Morita
Toshisuke
T
Department of Laboratory Medicine, Toho University, School of Medicine, 6-11-1, Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan. toshimrt@med.toho-u.ac.jp
Imai
Tomihiko
T
Sugiyama
Takao
T
Katayama
Shigehiro
S
Yoshino
Gen
G
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D003331:Coronary Vessels / Q000201:enzymology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004305:Dose-Response Relationship, Drug; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006965:Hyperplasia; D028421:Isoprostanes / Q000652:urine; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D014161:Transduction, Genetic; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014657:Vasculitis / Q000517:prevention & control
D028421:Isoprostanes; D008565:Membrane Proteins; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D003849:Deoxyguanosine