ROLE OF MAPKinases ON MOLECULAR MECHANISUMS OF CARDIOVASCULAR REMODELING

MAP激酶在心血管重塑分子机制中的作用

• 批准号: 14370036
• 负责人: IWAO Hiroshi
• 金额: $ 8.9万
• 依托单位: OSAKA CITY UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370036/
• 关键词: RENIN-ANGIOTENSIN SYSTEM; SIGNAL TRANSDUCTION; ORGAN DAMAGE; MAP KINASE; CARDIAC HYPERTROPHY; ANGIOTENSIN RECEPTOR ANTAGONIST; APOPTOSIS SIGNAL-REGULATING KINASE 1; Thy-1 NEPHRITIS; 病態モデル

The renin-angiotensin-aldosterone system (RAAS) plays an important role in both the physiological regulation of blood pressure and in the pathophysiological disruption of cardiovascular organ damages. Angiotensin II (Ang II) is the primary biological mediator of the RAAS. Pathophysiological actions of Ang II is mediated by the angiotensin II type I receptor, for examples of, vasoconstriction on vascular smooth muscle, secretion of aldosterone, reabsorption of sodium in the renal proximal nephron, and cell growth and proliferation.Treatments of RAAS inhibitors, angiotensin converting enzyme and Ang II type I receptor antagonist, in hypertensive rat models caused prevention effects of hypertension, cardiac hypertrophy, and vascular sclerosis and glomerular sclerosis. In addition, these effects were associated with suppressive gene expressions of TGF-b, collagen type I, collagen type II, fibronectin. These gene expressions were caused by the stimulation of Ang II type I receptor through the activation of mitogen activated protein kinases (ERK and JNK). Both angiotensin converting enzyme and Ang II type I receptor antagonist inhibited the activation of ERK and JNK.In this study, we investigated the role of apoptosis signal-regulating kinase 1 (ASK-1),ERK,JNK,p38 and activated protein 1 (AR 1) on cardiovascular organ damages. Furthermore, transcriptome analysis of glomerulus was performed in Thy-1 glomerular nephritis model. ASK-1,ERK,JNK,p38 and AP-1 are crossly related to the cardiac hypertrophy, vascular neointimal hyperplasia and glomerular damages. These results suggested that MAP Kinases family is proposed to be a potential therapeutic target for cardiovascular diseases.

肾素-血管紧张素-醛固酮系统（RAAS）在血压的生理调节和心血管器官损伤的病理生理破坏中起重要作用。血管紧张素II（AngII）是RAAS的主要生物介质。血管紧张素II的病理生理作用是由血管紧张素II I型受体介导的，例如，对血管平滑肌的血管收缩、醛固酮的分泌、肾近端肾单位中钠的重吸收以及细胞生长和增殖。以及血管硬化和肾小球硬化。此外，这些作用还与抑制TGF-b、I型胶原、II型胶原、纤连蛋白的基因表达有关。这些基因的表达是由Ang II I型受体通过激活丝裂原活化蛋白激酶（ERK和JNK）的刺激引起的。血管紧张素转换酶和血管紧张素Ⅱ Ⅰ型受体拮抗剂均能抑制ERK和JNK的激活。本研究探讨了凋亡信号调节激酶1（ASK-1）、ERK、JNK、p38和活化蛋白1（AR 1）在心血管损伤中的作用。此外，在Thy-1肾小球肾炎模型中进行肾小球的转录组分析。ASK-1、ERK、JNK、p38、AP-1与心肌肥厚、血管新生内膜增生、肾小球损伤等密切相关。这些结果提示MAP激酶家族可能成为心血管疾病治疗的潜在靶点。

项目成果

Zhan, Y., Kim, S., Izumi, Y., Izumiya, Y., Nako, T., Miyazaki, H., Iwao, H.: "Role of JNK, p38, and ERK in Platelet-Derived Growth Factor-Induce Vascular Proliferation, Migration, and Gene Expression"Arterioscler.Thromb.Vasc.Biol.. 23. 795-801 (2003)

Zhan, Y.、Kim, S.、Izumi, Y.、Izumiya, Y.、Nako, T.、Miyazaki, H.、Iwao, H.：“JNK、p38 和 ERK 在血小板衍生生长因子中的作用

Kim, S., Izumi, Y., Izumiya, Y., Zhan, Y., taniguchi, M., Iwao, H.: "Beneficial Effects of Combined Blockade of ACE and AT 1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery"Arterioscler.Thromb.Vasc.Biol.. 22. 1299-1304 (2002)

Kim, S.、Izumi, Y.、Izumiya, Y.、Zhan, Y.、taniguchi, M.、Iwao, H.：“联合阻断 ACE 和 AT 1 受体对球囊损伤大鼠内膜增生的有益作用

Zhan, Y., Kim, s., Yasumoto, H., Namba, M., Miyazaki H., Iwao, H.: "Effects of Dominant-Negative c-Jun on Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cell Proliferation"Arterioscler.Thromb.Vasc.Biol.. 22. 82-88 (2002)

Zhan, Y.、Kim, s.、Yasumoto, H.、Namba, M.、Miyazaki H.、Iwao, H.：“显性阴性 c-Jun 对血小板衍生生长因子诱导的血管平滑肌细胞的影响

Y.Izunmiya, 他7名: "Apoptosis signal-regulating kinase 1 plays a pivotal role in Angiotensin-II-induced cardiac hypertrophy and remodeling"Circulation Research. 93. 874-883 (2003)

Y. Izumiya 等 7 人：“细胞凋亡信号调节激酶 1 在血管紧张素 II 诱导的心脏肥大和重塑中发挥关键作用”循环研究 93. 874-883 (2003)。

S.Kim, 他5名: "Beneficial effects of combined blockade of ACE and AT1 receptor on intimal hyperplasia in balloon-injured rat artery"Arterioscler Thromb Vasc Bio. 22. 1299-1304 (2002)

S. Kim 等 5 人：“联合阻断 ACE 和 AT1 受体对球囊损伤大鼠动脉内膜增生的有益作用”Arterioscler Thromb Vasc Bio。