| Co-Investigator(Kenkyū-buntansha) |
EGUCHI Hironobu Hyogo College of Medicine, Research Associate, 医学部, 助手 (60351798)
YAMAGUCHI Yukihiro Hyogo College of Medicine, Research Associate, 医学部, 助手 (60330453)
OOKAWARA Tomomi Hyogo College of Medicine, Assistant Professor, 医学部, 講師 (50330452)
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| Research Abstract |
Nitric oxide (NO) serves as an important signal transducer in several cells and tissues, including blood vessels and neuronal and for smooth muscle cells, and its anti-apoptotic effect hematopoietic cells. It is generally thought that NO is involved in the regulation of a wide variety of biological processes, including smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation, immune regulation, and cellular differentiation.
Heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is produced in smooth muscle cells as well as the macrophages of atherosclerotic plaques and plays an important role in atherogenesis. Recent studies have shown that pro-HB-EGF, a membrane-anchored precursor, may promote the survival of renal epithelial and hepatoma cells.
In this study, we describe the effect of nitric oxide (NO) on the expression of the heparin-binding EGF-like growth factor (HB-EGF), a potent chemoattractant and mitogen for
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smooth muscle cells, and its anti-apoptotic effect against NO cytotoxicity. Previous studies have shown that glutathione peroxidase (GPx), a major peroxide scavenging enzyme is selectively inactivated by an NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), in vitro and in vivo and results in the accumulation of peroxide. The SNAP or peroxynitrite induces HB-EGF through the inactivation of GPx and the accumulation of peroxide. This induction is accompanied by JNK and c-Jun/AP-1 activation. The blocking of the HB-EGF induction by curcumin, c-jun antisense oligonucleotide, and a dominant-negative mutant of JNK1 provides support for these results. A longer pretreatment of rat aortic smooth muscle cells (RASMCs) by SNAP, induces HB-EGF and reduces the TNF-+actinomycin D-induced apoptosis. This protection is blocked by an tisense HB-EGF soligonucleotide. These findings indicate that the induction of HB-EGF by NO would be an adaptive response as an autocrine protective factor againsapoptosis by NO in RASMCs. Less
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