| Budget Amount *help |
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥900,000 (Direct Cost: ¥900,000)
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| Research Abstract |
Surivival and proliferation of human blood vessel endothelial cells (HBVEC) are influenced by fibroblast growth factor (FGF). Removal of FGF from the medium of the cells in culture resulted in death of the cells. The death caused by deprivation of FGF is active death (apoptosis), and the process of apoptosis can be inhibited by cycloheximide. Other mitogenic agents, such asEGF,PDGF,TGFs, ILl, and transferrin can not stop the HBVEC apoptosis. The effect of FGF is mimicked by a phorbol ester and is prevented by an inhibitor of protein kinase C.This mechanism is though to be important for the regulation of vascular organization through the degeneation of vessels. As smooth muscle cells produce FGFs, it seems that HBVEC accect the FGFs and survive from the smooth muscle cells like a paracrine fashion in vivo conditions. Several substances also induce or modify apoptosis on HBVEC.Hemorrhagic snake venoms induce apoptotic cell death, but neurotoxic snake venoms do no induce programd cell dea
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th. No effect of hemorrhagci venom is observed with many types of cultured cells other than HBVEC.Hemorrhagic snake venom appears to be a useful tool for studies of molecular mechanisms of vascular apoptosis. Addition of the alkyllysophodpholipid ET16-OMe, a putative antitumor drug, to the culture of HBVEC results in apoptotic cell death. The mechanism responsible of apoptosis induced by this drug has unique characteristics, as compared to those of apoptosis induced by other antitumor drugs, since the drug caused fragmentation of dying cells and its effect can be overcome by the presence of a survival factor, namely, FGF.Nitric oxide synthase (NOS) activity is enhanced in HBVEC by the combined stimulation of IFN-_Y plus IL-1beta, gamma TNF-alpha and PLS.The enhanced NOS production is associated with the death of the cells. NOS inhibitors such as nitro-L-arginine enhance survival of HBVEC.DNA analysis of the NOS induced HBVEC shows that internucleosomal DNA fragmentation has occurred, suggesting that apoptosis is at least partially induced by the excess NO production. Less
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