Investigation of intrinsic factors for angiogenesis and recovery of endothelial cell injury contributed to the convalescenc of ischemic heart disease

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We previously reported that tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase(NOS), has a regulatory role in nitric oxide (NO) production by nitric oxide synthase (N0S), and exogenous BH4 protects endothelial cell(EC) injury induced by reactive oxygen species (ROS) which were produced by intracellular BH4 reduction (Ishii et al., 1998). Moreover, the protective effect of BH4 seems to involve ROS scavenging activity and/or antioxidative activity. (Ishii. et al., 1997, Shimizu et al., 1998). BH4 also induced in vitro angiogenesis in vascular endothelial cell (Shimizu, et al., 1999). Therefore, it is possible that BH4 effectively ameliorates pathophysiological state induced by ROS, such as ischemia-reperfusion. First, we investigated the protective effects of BH4 in endothelial cell injury induced by infiltrated polymorphonuclear leukocytes (PMNs). Addition of BH4 to endothelial cells reduced PMN-induced EC injury. Second, we evaluated the involvement of PMN adhesion to endothelial cells in angiogenesis, because PMN infiltration was often observed around the neovascular vessels in ischemic tissue. Sublethal numbers of PMNs induced angiogenesis in vivo and in vitro, and that mechanism of stimulation of angiogenesis by PMNs may involve the adherence of PMNs to endothelial cells via E-selectin and intercellular adhesion molecule- 1(ICAM-l), and H_2O_2. Thus it is possible that BH4 inhibits tissue injury after ischemia-reperfusion. Hence, the protective effects of BH4 were investigated in rat gastric ischemia-reperfusion model and rat cardiac infarction model. Treatment of BH4 reduced tissue injury such as gastric ulcer or cardiac infarction in ischemia-reperfusion. These results demonstrated that BH4 is able to protect tissue injury after ischemia-reperfusion and the part of mechanisms for the protective effect was related with encouragement of angiogenesis induced by PMNs.