Role of ASK1 in Molecular Mechanism of Cardiovascular Diseases

ASK1在心血管疾病分子机制中的作用

• 批准号: 14570083
• 负责人: MITSUYAMA Sokei
• 金额: $ 2.3万
• 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 (C)
• 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-14570083/
• 关键词: angiotensin II; cardiac hypertrophy; vascular intimal thickening; gene deficient mouse; growth; migration; cardiovascular disease; シグナル伝達系; 血管肥厚; アポトーシス; 遺伝子導入; シグナル伝達

Apoptosis signal-regulated kinase 1 is a serine-threonine kinase, which plays a pivotal role in cell apoptosis, survival, and differentiation. Therefore, we investigated the possible role of ASK1 in cardiovascular diseases. We infused angiotensin II to rats, to study the role of ASK1 in cardiac hypertrophy. Dominant negative mutant of ASK1 gene transfer to cardiac tissue was performed with adenoviral vector and we examined the effect on cardiac INK and P38 activities, and cardiac hypertrophy and gene expression. We found that adenoviral infection of dominant negative ASK1 significantly prevented angiotensin II-induced pathologic cardiac hypertrophy. Furthermore, we also investigated the contribution of ASK1 to cardiac disease, using ASK1 deficient mice. Angiotensin II infusion to wild type mice caused activation of JNK and P38, cardiac hypertrophy, cardiac phenotype-and remodeling-associated gene expression, interstitial fibrosis, and coronary arterial remodeling. And all these effects … More of angiotensin II in wild type mice were significantly lessened in ASK1 deficient mice. These results show that ASK1 plays the crucial role in pathologic cardiac hypertrophy induced by angiotensin II. Besides the role of ASK1 in cardiac disease, we studied the contribution of ASK1 to vascular disease. Gene transfer of dominant negative mutant of ASK1 to rat carotid artery significantly prevented balloon injury-induced vascular smooth muscles cell proliferation and migration, leading to the significant prevention of vascular intimal hyperplasia. This inhibitory effect of dominant negative mutant of ASK1 on intimal hyperplasia was mediated by inhibition of JNK and P38 activations. Furthermore, we investigated the role of ASK1 in vascular remodeling, using ASK1 deficient mice. Cuff injury of femoral artery in wild type mice induced the significant thickening of vascular intimal and this intimal hyperplasia in wild type mice was significantly reduced in ASK1 deficient mice. We also compared between vascular smooth muscle cells from ASK1 deficient mice and wild type mice, regarding proliferation and migration. We noted that the proliferation and migration of vascular smooth muscle cells from ASK1 deficient mice were significantly decreased compared with those from wild type mice. These results indicate that ASK1 is implicated in vascular remodeling. Thus, ASK1 is responsible for the molecular mechanism of cardiovascular diseases and seems to be the promising therapeutic target for cardiovascular disease. Less

凋亡信号调节激酶1是一种丝氨酸-苏氨酸激酶，在细胞凋亡、存活和分化中起关键作用。因此，我们研究了ASK1在心血管疾病中的可能作用。我们给大鼠注入血管紧张素II，研究ASK1在心肌肥厚中的作用。用腺病毒载体将ASK1基因显性负突变体转移到心脏组织，检测其对心脏INK和P38活性、心肌肥厚和基因表达的影响。我们发现显性阴性ASK1的腺病毒感染可显著预防血管紧张素ii诱导的病理性心肌肥大。此外，我们还利用ASK1缺陷小鼠研究了ASK1对心脏病的贡献。血管紧张素II输注野生型小鼠引起JNK和P38的激活、心脏肥大、心脏表型和重塑相关基因表达、间质纤维化和冠状动脉重塑。在ASK1缺陷小鼠中，野生型小鼠的血管紧张素II明显减少。这些结果表明，ASK1在血管紧张素II诱导的病理性心肌肥大中起着至关重要的作用。除了ASK1在心脏疾病中的作用，我们还研究了ASK1在血管疾病中的作用。将ASK1显性负突变体基因转移至大鼠颈动脉，可显著阻止球囊损伤诱导的血管平滑肌细胞增殖和迁移，从而显著预防血管内膜增生。ASK1显性负突变体对内膜增生的抑制作用是通过抑制JNK和P38的激活来介导的。此外，我们利用ASK1缺陷小鼠研究了ASK1在血管重构中的作用。野生型小鼠股动脉袖带损伤引起血管内膜明显增厚，ASK1缺陷小鼠的血管内膜增生明显减少。我们还比较了ASK1缺陷小鼠和野生型小鼠血管平滑肌细胞在增殖和迁移方面的差异。我们注意到，与野生型小鼠相比，ASK1缺陷小鼠血管平滑肌细胞的增殖和迁移明显减少。这些结果表明ASK1与血管重塑有关。因此，ASK1参与心血管疾病的分子机制，似乎是有希望的心血管疾病治疗靶点。少

项目成果

Izumiya Y, Kim S, Izumi Y, Yoshida K, Yoshiyama M, Matsuzawa A, Ichijo H, Iwao H: "Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induces cardiac hypertrophy and remodeling."Circ Res.. 93. 874-883 (2003)

Izumiya Y、Kim S、Izumi Y、Yoshida K、Yoshiyama M、Matsuzawa A、Ichijo H、Iwao H：“细胞凋亡信号调节激酶 1 在血管紧张素 II 诱导心脏肥大和重塑中发挥着关键作用。”Circ Res..

Omura T, Yoshiyama M, Kim S, Matsumoto R, Nakamura Y, Izumi Y, Ichijo H, Sudo T, Akioka K, Iwao H, Takeuchi K, Yoshikawa J.: "Involvement of apoptosis signal-regulating kinase-1 on angiotensin II-induced monocyte chemoattractant protein-1 expression."Arte

Omura T、Yoshiyama M、Kim S、Matsumoto R、Nakamura Y、Izumi Y、Ichijo H、Sudo T、Akioka K、Iwao H、Takeuchi K、Yoshikawa J.：“凋亡信号调节激酶 1 对血管紧张素 II 的参与

Zhan Y, Kim S, Izumi Y, Izumiya Y, Nakao T, Miyazaki H, Iwao H.: "Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression."Arterioscler Thromb Vasc Biol.. 23. 795-801 (2003)

Zhan Y、Kim S、Izumi Y、Izumiya Y、Nakao T、Miyazaki H、Iwao H.：“JNK、p38 和 ERK 在血小板衍生生长因子诱导的血管增殖、迁移和基因表达中的作用。”

Kawano H, Kim S, Ohta K, Nakao T, Miyazaki H, Nakatani T, Iwao H.: "Differential contribution of three mitogen-activated protein kinases to PDGF-BB-induced mesangial cell proliferation and gene expression."J Am Soc Nephrol.. 14. 584-592 (2003)

Kawano H、Kim S、Ohta K、Nakao T、Miyazaki H、Nakatani T、Iwao H.：“三种丝裂原激活蛋白激酶对 PDGF-BB 诱导的系膜细胞增殖和基因表达的不同贡献。”J Am Soc Nephrol

金 勝慶: "心疾患と局所レニン・アンジオテンシン系"病理と臨床. 845-852 (2003)

Katsuyoshi Kim：“心脏病和局部肾素-血管紧张素系统”病理学和临床实践845-852（2003）。