Mechanism of arteriosclerosis evoked by production and processing of HB-EGF induced by nitric oxide

一氧化氮诱导HB-EGF生产加工诱发动脉硬化的机制

• 批准号: 13670151
• 负责人: SUZUKI Keiichiro
• 金额: $ 1.98万
• 依托单位: Hyogo College of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670151/
• 关键词: Nitric oxide; HB-EGF; arterioselerosis; reactive oxygen species; smooth muscle cells; JNK; アポトーシス; HP-EGF

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 … More 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

一氧化氮（NO）是血管、神经元、平滑肌细胞等多种细胞和组织的重要信号换能器，对造血细胞具有抗凋亡作用。一般认为NO参与多种生物过程的调节，包括平滑肌松弛、神经传递、抑制血小板聚集、免疫调节和细胞分化。肝素结合EGF样生长因子（Heparin-binding EGF-like growth factor, HB-EGF）是表皮生长因子（epidermal growth factor， EGF）家族的一员，在动脉粥样硬化斑块的平滑肌细胞和巨噬细胞中产生，在动脉粥样硬化发生中起重要作用。最近的研究表明，前hb - egf，一种膜锚定的前体，可能促进肾上皮细胞和肝癌细胞的存活。在这项研究中，我们描述了一氧化氮（NO）对肝素结合的egf样生长因子（HB-EGF）表达的影响，以及一氧化氮对平滑肌细胞的抗凋亡作用。先前的研究表明，谷胱甘肽过氧化物酶（GPx）是一种主要的过氧化物清除酶，在体外和体内被NO供体s -亚硝基-n -乙酰基- dl -青霉胺（SNAP）选择性失活，导致过氧化物积累。SNAP或过氧亚硝酸盐通过GPx的失活和过氧化物的积累诱导HB-EGF。这种诱导伴随着JNK和c-Jun/AP-1的激活。姜黄素、c-jun反义寡核苷酸和JNK1的显性阴性突变体对HB-EGF诱导的阻断为这些结果提供了支持。通过SNAP对大鼠主动脉平滑肌细胞（RASMCs）进行较长时间的预处理，可诱导HB-EGF，减少TNF-+放线菌素d诱导的细胞凋亡。这种保护作用被一种酶感HB-EGF单核苷酸阻断。这些发现表明，NO诱导HB-EGF可能是一种适应性反应，是一种自分泌保护因子，可抵抗NO在RASMCs中的凋亡。少

项目成果

Koh, Y.H.et al.: "Inactivation of glutathione peroxidase by No leads to the accumulation of H2O2 and the induction of HB-EGF via c-Jun NH2-terminal kinase in rat aortic smooth muscle cells"FASEB J.. 15. 1472-1474 (2001)

Koh, Y.H. 等人：“No 灭活谷胱甘肽过氧化物酶会导致 H2O2 积累，并通过大鼠主动脉平滑肌细胞中的 c-Jun NH2 末端激酶诱导 HB-EGF”FASEB J.. 15. 1472-

Koh YH, et al.: "Osmotic stress induces HB-EGF gene expression via Ca2+/JNK signal cascades in rat aortic smooth muscle cells"J Biochem.. 130. 351-358 (2001)

Koh YH 等人：“渗透应激通过大鼠主动脉平滑肌细胞中的 Ca2 /JNK 信号级联诱导 HB-EGF 基因表达”J Biochem.. 130. 351-358 (2001)

Eguchi H, et al.: "Oxidative Damage Due to Copper Ion and Hydrogen Peroxide Induces GlcNAc-Specific Cleavage of an Asn-Linked Oligosaccharide"J.Biochem. 131. 477-484 (2002)

Eguchi H 等人：“铜离子和过氧化氢引起的氧化损伤诱导 Asn 连接寡糖的 GlcNAc 特异性裂解”J.Biochem。

Park YS, et al.: "Identification of the Binding Site of Methylglyoxal on Glutathione Peroxidase : Methylglyox al Inhibits Glutathione Peroxidase Activity via Binding to Glutathione Binding Sites Arg 184 and 185"Free Rad. Res.. 37. 205-211 (2002)

Park YS 等人：“谷胱甘肽过氧化物酶上甲基乙二醛结合位点的鉴定：甲基乙二醛通过与谷胱甘肽结合位点 Arg 184 和 185 结合来抑制谷胱甘肽过氧化物酶活性”Free Rad。

Yamamoto K, et al.: "Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart"Cardiovasc.Res.. 55. 76-82 (2002)

Yamamoto K 等人：“心肌僵硬度是由心室纤维化决定的，而不是由高血压心脏的代偿性或过度肥厚决定的”Cardiovasc.Res.. 55. 76-82 (2002)