Development of intracellular therapy to induce a regression of coronary arteriosclerotic lesions

开发诱导冠状动脉硬化病变消退的细胞内疗法

• 批准号: 10357006
• 负责人: TAKESHITA Akira
• 金额: $ 23.42万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10357006/
• 关键词: arteriosclerossis; coronary artery; ischemic heart disease; Rho-kinase; signal transduction; coronary vasospasm; regression; サイトカイン; 冠攣縮; Rhoーkinase; 動脈硬化の退縮

1. In the porcine femoral arteries injured by balloon technique, Rho-kinase was upregulated both at the mRNA and activity levels. The in vivo gene transfer of dominant-negative Rho-kinase (DNRhoK) significantly inhibited the development of the balloon injury-induced vascular lesions.2. The long-term treatment of the porcine coronary artery from the adventitial with MCP-1 and Ox-LDL caused a development of arteriosclerotic lesions (intimal thickening and geometric remodeling). The long-term blockade of Rho-kinase with hydroxyfasudil significantly suppressed the development of those vascular lesions.3. The long-term treatment of the porcine coronary artery from the adventitial with IL-1β caused a development of arteriosclerotic lesions (intimal thickening and geometric remodeling). The long-term blockade of Rho-kinase with hydroxy fasudil caused a regression of those vascular lesions in vivo.4. The in vivo gene transfer of DNRhoK induced a regression of constrictive remo deling in a porcine model with IL-1b/These results indicate that Rho-kinase is substantially involved in the pathog enesis of coronary arteriosclerosis and that the long-term inhibition of the molecule could induce a regression of the arterioclerotic vascular lesions.

1.在球囊损伤的猪股动脉中，Rho-Kinase在mRNA和活性水平均有上调。结论：1.体内转导显性负性Rho-Kinase(DNRhoK)基因可显著抑制球囊损伤后血管病变的发生发展。猪冠状动脉外膜长期应用单核细胞趋化蛋白-1和氧化低密度脂蛋白可导致动脉粥样硬化病变(内膜增厚和几何重构)。用羟法舒地尔长期阻断Rho-Kinase可显著抑制这些血管病变的发展。长期应用IL-1β处理猪冠状动脉外膜，可导致动脉粥样硬化病变(内膜增厚和几何重构)。用羟基法舒地尔长期阻断Rho-Kinase可使这些血管病变在活体内消退。体内转导DNRhoK基因可引起猪IL-1b缩窄Remo-Deling的消退。这些结果表明，Rho-Kinase在冠状动脉硬化的发病机制中起重要作用，长期抑制该分子可诱导动脉粥样硬化血管病变的消退。

项目成果

Shimokawa H.: "Proceedings of the International Symposium of Coronary Artery Spasm. (Yasue H,ed.)"Axel Springer Japan Publishing Inc.. 100(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.. 100(91-95) (2000)

Miyata K,Shimokawa H,Takeshita A.: "Lipoprotein Metabolism and Atherosclerosis. (Kita T, Yokode M,eds.)"Springer-Verlag,Tokyo.. 259(269-271) (2000)

Miyata K，Shimokawa H，Takeshita A.：“脂蛋白代谢和动脉粥样硬化。（Kita T，Yokode M，编辑）”Springer-Verlag，东京.. 259（269-271）（2000）

Mukai Y,Shimokawa H,Matoba T, et al.: "Involvement of Rho-kinase in hypertensive vascular disease. -A novel therapeutic target in hypertension-"FASEB Journal. (In press.). (2000)

Mukai Y、Shimokawa H、Matoba T 等人：“Rho 激酶参与高血压血管疾病。-高血压的新治疗靶点-”FASEB 杂志。

Momii H et al.: "Inhibition of adhesion molecules markedly ameliorates cytokine-induced sustained myocardial dysfunction in dogs vivo." Joumal of Molecular and Cellular Cardiology. 30. 2637-2650 (1998)

Momii H 等人：“抑制粘附分子可显着改善狗体内细胞因子诱导的持续心肌功能障碍。”

Eto Y,Shimokawa H,Hiroki J, et al.: "Gene transfer of dominant-negative Rho-kinase suppresses neointimal formation after balloon injury in pigs."American Journal of Physiology. 278. H1744-H1750 (2000)

Eto Y、Shimokawa H、Hiroki J 等人：“显性失活 Rho 激酶的基因转移可抑制猪球囊损伤后的新内膜形成。”美国生理学杂志。