|Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1996: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1995: ¥1,900,000 (Direct Cost: ¥1,900,000)
Oxidative stress is considered to play an important role in the progression of neointimal formation after balloon injury as well as atheromatous lesions. The induction of heme oxygenase-1 (HO-1), conpled to ferritin synthesis, is a rapid protective antioxidant response. This enzyme has been shown to increase following oxidative stress in various cell lines. We found that intraperitoneal (i.p.) injection of hemin, 30 mg/kg, for 5 days upregulated HO-1 mRNA) and protein levels in rat carotid artery. To examine if upregulation of endogenous HO-1 suppresses neointimal formation, rats were given i.p.hemin injection for 5 days and underwent balloon injury on the third day of injection. We also examined if Sn protoporphyrin, an antagonist of HO-1, could reverse the effect of hemin, Sn protoporphyrin (10mg) was topically applied around the balloon-injured carotid artery using pluronic gel. Rats were sacrificed and examined 2 weeks after balloon injury.
We demonstrated that induction of endogeno
us HO-1 effectively suppressed the neointimal proliferation of the balloon-injured rat carotid artery. These findings suggest that oxidative stress palys an important role in neointimal formation after balloon injury.
We evaluated its effect on fatty plaque formation on the aortae of high-cholesterol fed rabbits by using hemin 2.0kg male white rabbits were fed with a chow containing 1.5% cholesterol (Cho) for four weeks. Cho-rabbits were divided into four groups : (1)saline ip [intraperitoneal injection], n=4 (2) Hemin 30mg/kg ip, n=5(3) saline ip +Tin-protoporphyrin (TPP : HO-1inhibitor) 7mg/kg sc [subcutaneous injection], n=5 (4) Hemin 30mg/kg ip+TPP7mg/kg sc, n=5(all ip & sc done every three days) Fatty plaque area (FPA) dyed with Sudan III was measured and expressed as the ratio to whole area of aorta. Aortic ring was examined in organ chamber on its maximum response to acetylcholine after contraction with noradrenaline to evaluate endothelium-deriived relaxation (EDR). Hemin-induced HO-1 expression in aorta and liver was confirmed with Northern blot analysis. There were no difference in body weight, serum cholesterol, and blood pressure among four groups at sacrifice. FPA decreased with Hemin, increased with TPP : (1)9.5+2.4(2)2.4+1.5(3)15.2+5.2(4)3.2+0.7(mean+SE)%.Cho-rabbits showed smaller EDR than usual chow rabbits. Hemin improved EDR and TPP weakened its effect : (1)20.0+8.4(2)55.4+7.9(3)17.8+4.6(4)37.5+8.3(mean+SE)%.These data suggest that HO-1 pathway has the important role in defending against atherogenesis. Less