title: Effects of induction/inhibition of endogenous heme oxygenase-1 on lipid metabolism, endothelial function, and atherosclerosis in rabbits on a high fat diet.
abstract: The heme oxygenase-1 (HO-1) / carbon monoxide (CO) system has been presumed as a therapeutic target for preventing atherosclerosis. However, the exact mechanism(s) underlying this system remains largely undefined. This study aims to examine the influence of induction/inhibition of HO-1 on atherosclerotic plaque using pharmacological approaches and to elucidate potential mechanisms. Rabbits were randomly assigned to receive a standard diet (control group), high fat diet (HFD), HFD plus HO inducer hemin (HFD + H group), and HFD plus an HO inhibitor, zinc protoporphyrin-9 (ZnPP9, HFD + Z group). Atherosclerotic plaque was evaluated using oil red O staining and histological analyses. Immunohistochemistry, western blotting, and RT-PCR were employed to study the expression of HO-1 and endothelin-1 (ET-1). Levels of CO, nitric oxide (NO), eNOS/iNOS activities, NF-κB activity, and TNF-α level were determined. No significant differences of serum lipid levels were observed among the HFD, HFD + Z, and HFD + H groups. In rabbits, HFD induced typical atherosclerotic plaque and increased intima/media thickness ratio, which was markedly reduced in the HFD + H group and further aggravated in the HFD + Z group. Furthermore, hemin increased HO-1 expression, CO levels, and eNOS activity, while decreasing iNOS levels, ET-1 expression, NF-κB activity, and TNF-α level. ZnPP9 caused opposite effects. Induction of the endogenous HO-1/CO system by hemin can prevent atherosclerosis though increasing CO levels, regulating eNOS activity, NF-κB activity, TNF-α levels, and ET-1 levels in rabbits. Our results add new evidence for the importance of HO-1 in the genesis and development of atherosclerosis and provide several possible mechanisms underlying the anti-atherosclerosis effects of HO-1.
authors.affiliation: Department of Cardiology, The Affiliated Hospital of Guiyang Medical College, China. Liudanan2000@yahoo.com.cn
authors.forename: Danan
authors.initials: D
authors.lastname: Liu
authors.forename: Zuoyun
authors.initials: Z
authors.lastname: He
authors.forename: Lirong
authors.initials: L
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D019332:Endothelin-1 / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D050356:Lipid Metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D016328:NF-kappa B; D011524:Protoporphyrins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C017803:zinc protoporphyrin; D009569:Nitric Oxide; D006427:Hemin; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1