Experimental and Clinical Studies on the Role of Inflammatory Mechanisms in the Pathogenesis of Ischemic Heart Disease

炎症机制在缺血性心脏病发病机制中作用的实验和临床研究

• 批准号: 09470169
• 负责人: SHIMOKAWA Horoaki
• 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: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470169/
• 关键词: cytokines; atherosclerosis.; coronary artery spasm; vascular remodeling; nitric oxide; small G proteins; Rho-kinase; gene therapy; Rho-kinase; 炎症性サイトカイン; 虚血性心疾患; マクロファージ; 血管外膜; 炎症; 冠攣縮

(Experimental studies)1. The long-term adventitial treatment with IL-1βresulted in the development of vascular remodeling and neointimal formation of the porcine coronary artery in vivo, whereas endothelial vasodilator functions were fairly preserved.2. In this porcine model, inducible NO synthase (iNOS) was transiently expressed in VSMC and exerted an inhibitory effect against vascular lesion formation in vivo.3. Regarding the molecular mechanism of the coronary artery spasm in this porcine model, it was shown that Rho-kinase is upregulated and inhibits myosin phosphatase, resulting in the increased myosin phosphorylations and hypercontractions of VSMC.4. We have established the method of in vivo gene transfer into the coronary artery in vivo using the infiltrator balloon angioplasty catheter (IABC). Using this novel method, we were able to inhibit the neointimal formation after balloon injury in porcine coronary arteries by overexpressing CNP in vivo.5. The long-term inhibitation of Rho-kinase by either hydroxyfasudil (a specific inhibitor of Rho-kinase) or in vivo gene transfer of dominant negative Rho-kinase resulted in the regression of vascular remodeling caused by inflammatory cytokines.(Clinical studies)In patients with coronary artery disease, the plasma levels of macrophage-colony stimulating factor (M-CSF) were increased while those of transforming factor-b (TGF-b) were decreased, thus stimulating the process of atherosclerosis.

（实验研究）1。结论：1. IL-1β长期外膜处理可导致猪冠状动脉血管重塑和新生内膜形成，而内皮舒张功能明显减弱.诱导型一氧化氮合酶（inducible NO synthase，iNOS）在猪血管平滑肌细胞中瞬时表达，并对血管损伤的形成具有抑制作用.关于该猪模型中冠状动脉痉挛的分子机制，研究表明Rho激酶上调并抑制肌球蛋白磷酸酶，导致肌球蛋白磷酸化增加和VSMC过度收缩。我们已经建立了体内基因转移到体内冠状动脉使用infiltrator球囊血管成形术导管（IABC）的方法。使用这种新的方法，我们能够通过在体内过表达CNP来抑制猪冠状动脉球囊损伤后的新生内膜形成. Rho激酶的特异性抑制剂羟基法舒地尔（hydroxyfasudil）对Rho激酶的长期抑制作用或显性负性Rho激酶的体内基因转移均导致炎性细胞因子引起的血管重塑消退。冠心病患者血浆中巨噬细胞集落刺激因子（M-CSF）水平升高，转化因子-b（TGF-b）水平降低，从而刺激动脉粥样硬化的进程。

项目成果

Fukumoto, Y., Shimokawa H., et al.: "Vasculoprotecvite role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1β in pigs in vivo"Circulation. 96. 3104-3111 (1997)

Fukumoto，Y.，Shimokawa H.，等人：“诱导型一氧化氮合酶对猪体内白细胞介素-1β慢性治疗引起的炎症性冠状动脉损伤的血管保护作用”循环。

Shimokawa H.: "Intracellular mechanisms for coronary artery spasm." R.G.Randes Co(in press),

Shimokawa H.：“冠状动脉痉挛的细胞内机制。”

Fukumoto Y, Shimokawa H, et al.: "Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1b in pigs in vivo."Circulation. 96. 3104-3111 (1997)

Fukumoto Y、Shimokawa H 等人：“诱导型一氧化氮合酶对猪体内白细胞介素 1b 长期治疗引起的炎症性冠状动脉病变的血管保护作用。”循环。

Shimokawa H.: "Molecular Mechanisms of Smooth Muscle Contraction,"R. G. Landes Co.. 107-117 (1999)

Shimokawa H.：“平滑肌收缩的分子机制”，R.

Oyama J et al.: "Role of nitric oxide and paroxynitrite in the cytokine-induced myocardial dysfunction in dogs in vivo." Journal of Clinical Investigation. 101. 2207-2214 (1998)

Oyama J 等人：“一氧化氮和聚亚硝酸盐在细胞因子诱导的狗体内心肌功能障碍中的作用。”