Heme Oxygenase-1 in Vascular Smooth Muscle Cells Counteracts Cardiovascular Damage Induced by Angiotensin II

Abstract

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.