Interaction between AT1 and β-adrenergic receptors affects redox-sensitive intracellular signal transduction in heart

AT1和β-肾上腺素能受体之间的相互作用影响心脏氧化还原敏感的细胞内信号转导

基本信息

批准号：
17590220
负责人：
KIMURA Shoji
金额：
$ 2.3万
依托单位：
Kagawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590220/
关键词：
Angiotensin Adrenergic receptor 心肥大酸化ストレス

项目摘要

Elevated activities of the sympathetic nerve and renin-angiotensin systems are common features of heart failure. This study aimed to examine the involvement of interaction between AT1 and β-adrenergic receptors in redox-sensitive signal transduction in the failing heart. Chronic isoproterenol (ISO) infusion to mice caused concentric cardiac hypertrophy, accompanied by enhancement of cardiac collagen accumulation, lipid peroxidation, superoxide generation and NADPH oxidase activity. The AT1a and β-1,2 receptor mRNA expressions were down-regulated in the heart of ISO-infused mice. Simultaneous treatment of ARB markedly suppressed cardiac mass enlargement as well as increases of oxidative indicators without any effects on heart rate. The ATla receptor contribution to ISO-induced cardiac hypertrophy was reproduced in AT1aR-/-mice. These data suggest that the AT1 receptor plays a crucial role in the development of cardiac hypertrophy and oxidative stress under excessive β-adrenergic stimula … More tion, and that ARB treatment is beneficial for sympatho-excitatory cardiac hypertrophy and failure in mice.We also examined the effects of ARB on redox-sensitive activation of cardiac MAPK provoked by acute administration of ISO, resulting in the suppressive effects of ARB on ISO-induced MAP kinase activation. Analysis of the small GTPase regulating Raf activity indicated that the mechanism by which ARB inhibits the Raf/MEK/ERK pathway under β-adrenergic receptor stimulation was basically dependent on changes in the activities of Ras (stimulatory) and Rap-1 (inhibitory to Raf cascade). Activities of Ras and Rap-1 in the heart were markedly augmented by ISO, whereas ARB suppressed only Ras activity, but not Rap-1 activity. Raf immunoprecipitation experiments confirmed that increases in its association with total and phosphorylated forms of MEK induced by ISO were completely normalized by ARB treatment. These results might provide a molecular basis for the beneficial effects of AT1 receptor antagonists on cardiac remodeling and functions in patients with sympatho-excitatory heart failure. Less

交感神经和肾素 - 血管紧张素系统的升高活动是心力衰竭的常见特征。这项研究旨在检查AT1和β-肾上腺素受体之间的相互作用参与失败心脏中对氧化还原敏感的信号转导。慢性异丙肾上腺素（ISO）输注小鼠引起同心心脏肥大，这是通过增强心脏胶原蛋白积累，脂质过氧化，超氧化物产生和NADPH氧化物活性来完成的。在注入ISO的小鼠的心脏中，AT1A和β-1,2受体mRNA表达下调。同时对ARB的治疗显着抑制了心脏质量扩张以及氧化指示剂的增加，而不会对心率产生任何影响。在AT1AR - / - 小鼠中再现了对ISO诱导的心脏肥大的ATLA受体贡献。这些数据表明，在过度的β-肾上腺素能刺激下，AT1受体在心脏肥大和氧化应激的发展中起着至关重要的作用……更多的是，ARB治疗对交感神经性心脏肥大和失败是有益的。在ISO诱导的MAP激酶激活上。对小型GTPase调节RAF活性的分析表明，在β-肾上腺素受体模拟下抑制RAF/MEK/ERK途径的机制基本上取决于RAS（刺激）和RAP-1的活性的变化（抑制RAF级联）。 ISO显着增强了RAS和RAP-1在心脏中的活动，而ARB仅抑制了RAS活动，但不抑制RAP-1活动。 RAF免疫沉淀实验证实，ISO诱导的MEK的总和磷酸化形式的增加，通过ARB处理完全归一化。这些结果可能为AT1受体拮抗剂对心脏重塑的有益作用提供了分子基础，并在交感神经性心力衰竭患者中的功能。较少的