Basic and clinical studies on the role of inflammatory mechanisms in the pathogenesis ischemic heart disease

炎症机制在缺血性心脏病发病机制中的基础与临床研究

• 批准号: 12470158
• 负责人: SHIMOKAWA Hiroaki
• 金额: $ 8.77万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470158/
• 关键词: Inflammation; Rho-kinase; Arteriosclerosis; Angiotensin II; Oxidative stress; 虚血性心疾患; 冠動脈攣縮; 冠動脈; 虚血性心臓病; 炎症性サイトカイン; マクロファージ; 血管リモデリング

1) Rho-kinase is substantially involved in the inflammatory mechanisms of arteriosclerosis. The expression of Rho-kinase in vascular smooth muscle cells is upregulated by inflammatory stimuli, such as angiotensin II and IL-1β with an involvement of Nf-_KB.2) Rho-kinase mediates hypoxia-induced downregulation of endothelial NO synthase (eNOS) in cultured human endothelial cells. Hydroxyfasudil, a specific Rho-kinase inhibitor, prevents the hypoxia-induced downregufayion of eNOS.3) Long-term inhibition of Rho-kinase suppresses in-stent restenosis in porcine coronary arteries, in which multiple mechanisms are involved, including enhancement of VSMC apoptosis, suppression of MCP-1 expression and inflammatory cell recruitment, and suppression of collagen synthesis through TGF-bl inhibition.4) Long-term inhibition of Rho-kinase suppresses angiotensin Il-induced formation of cardiovascular lesions by multiple mechanisms, including suppressions of NAD(P)H and TGF-β1 expression and of superoxide production.5) Long-term inhibition of Rho-kinase suppresses cardiac allograft vasculopathy, in which inhibition of the expression of macrophage migration inhibitory factor (MIF) is involved.

1) rho激酶实质上参与了动脉硬化的炎症机制。血管平滑肌细胞中rho激酶的表达在Nf-_KB参与的炎症刺激下上调，如血管紧张素II和IL-1β。2) rho激酶介导缺氧诱导的人内皮细胞内皮NO合成酶（eNOS）下调。羟法舒地尔是一种特异性rho激酶抑制剂，可防止缺氧诱导的eNOS下调。3)长期抑制rho激酶可抑制猪冠状动脉支架内再狭窄，其机制包括增强VSMC凋亡、抑制MCP-1表达和炎症细胞募集、通过抑制TGF-bl抑制胶原合成等。4)长期抑制rho激酶通过多种机制抑制血管紧张素il诱导的心血管病变的形成，包括抑制NAD(P)H和TGF-β1的表达以及超氧化物的产生。5)长期抑制rho激酶可抑制同种异体心脏移植血管病变，其中涉及抑制巨噬细胞迁移抑制因子（MIF）的表达。

项目成果

Masumoto A, Mohri M, Shimokawa H, et al.: "Suppression of coronary artery spasm by a Rho-kinase inhibitor in patients with vasospastic angina"Circulation. (in press). (2002)

Masumoto A、Mohri M、Shimokawa H 等人：“血管痉挛性心绞痛患者通过 Rho 激酶抑制剂抑制冠状动脉痉挛”循环。

Shimokawa H.: "Proceedings of the International Symposium of Coronary Artery Spasm.(Yasue H,ed.)"Axel Springer Japan Publishing Inc.. 91-95 (2000)

Shimokawa H.：“冠状动脉痉挛国际研讨会论文集。(Yasue H,ed.)”Axel Springer Japan Publishing Inc.. 91-95 (2000)

Takemoto M, et al.: "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase"Circulation. 106. 57-62 (2002)

Takemoto M 等人：“Rho 激酶介导缺氧诱导的内皮一氧化氮合酶下调”循环。

Masumoto A, Mohri M, Shimokawa H, et al.: "Suppression of coronary artery spasm by a Rho-kinase inhibitor fasudil in patients with vasospastic angina"Circulation. 105. 1545-1547 (2002)

Masumoto A、Mohri M、Shimokawa H 等人：“Rho 激酶抑制剂法舒地尔对血管痉挛性心绞痛患者的冠状动脉痉挛的抑制作用”。

Takemoto M, et al.: "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase."Circulation.. 106. 57-62 (2002)

Takemoto M 等人：“Rho 激酶介导缺氧诱导的内皮一氧化氮合酶下调。”Circulation.. 106. 57-62 (2002)