| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Kunio Department of Biochemstry, Osaka University, Associat Prof., 医学系研究科, 助教授 (90201780)
MORIGACH Atsvsh Department of Genatric Med. Osaka University, Associat Prof., 医学系研究科, 助手 (10273666)
HIGAKI Jitsuo Department of Genatric Med. Osaka University, Associat Professor, 医学系研究科, 助教授 (70189744)
TAIGI Mutsuo Sumitoro Pharmocoutul., 主任研究員
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| Research Abstract |
In this study, we investigated the role of hepatocyte growth factor (HGF) in the pathogenesis of cardiovascular disease. Initially, we focused on the application of therapeutic angiogenesis using HGF. The feasibility of a novel therapeutic strategy using angiogenic growth factors by expediting and /or augmenting collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of angiogenic growth factors whose mitogenic activity on endothelial cells is very potent. In this study, we hypothesized that transfection of HGF gene into ischemic hindlimb model could induce therapeutic angiogenesis in resonse to hypoxia.
At 3, 5 and 7 weeks after transfection, blood flow was significantly increased in hindlimb transfected with human HGF vector compared to control vector, accompanied by a significant increase in human HGF. The number of vessels around the injection sites of hindlimb transfected with HGF gene was sign
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ificantly increased as compared to control vector or vehicle. Interestingly, endogenous HGF concentration in ischemic hindlimb was significantly decreased as compared to non-ischemic hindlimb. Therefor, we reasoned that transfection of HGF gene into ischemic hindlimb could induce a beneficial response in response to the decreased endogenous HGF. Indeed, vascular HGF concentration in the diseased segments of vessels from patents with peripheral arterial disease was also significantly decreased as compared to disease-free segments from the same patients, accompanied by a marked reduction in HGF mRNA. Importantly, angiogenic property of HGF was also observed in diabetic rats. Here, we provide direct in vivo evidence for angiogenesis induced by transfection of human HGF gene in rat and rabbit ischemia hindlimb model, as potential "cytokine supplement therapy" for peripheral arterial disease. Currently, we submitted human gene therapy trail using HGF to treat peripheral arterial disease.
We also studied the possibility of serum HGF concentration as potential index of atherosclerosis. HGF might contribute to protection and/or repair of vascular endothelial cells injured by high blood pressure. Interestingly, serum HGF concentration in hypertensive paients with complications was significantly higher than that in hypertensive patients without complications and normotensive subjects. Moreover, serum HGF concentration in diabetic. patients with hypertensive complications was even higher than that in diabetics without complications. These data suggest that HGF may be considered as a new index of the severity of hypertension. Less
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