Effects of induction/inhibition of endogenous heme oxygenase-1 on lipid metabolism,endothelial function,and atherosclerosis in rabbits on a high fat diet

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 antiatherosclerosis effects of ho-1. © the japanese pharmacological society.