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

交感神经和肾素-血管紧张素系统活性升高是心力衰竭的常见特征。本研究旨在研究AT1和β肾上腺素能受体之间的相互作用在衰竭心脏氧化还原敏感信号转导中的作用。慢性注射异丙肾上腺素(ISO)可引起小鼠向心性心肌肥厚，并伴有心肌胶原堆积、脂质过氧化、超氧化物歧化和NADPH氧化酶活性增强。心肌AT1a和β-1，2受体基因表达下调。同时治疗ARB可显著抑制心脏重量增大和氧化指标的增加，而对心率没有任何影响。AT1aR-/-小鼠复制了ATLA受体在ISO诱导的心肌肥厚中的作用。这些数据表明，AT1受体在过度的β-肾上腺素能刺激…下的心肌肥厚和氧化应激的发展中起关键作用。我们还观察了ARB对ISO引起的心肌MAPK氧化还原敏感性激活的影响，从而抑制了ISO诱导的MAP激酶的激活。对调节Raf活性的小GTP酶的分析表明，ARb在β-肾上腺素能受体刺激下抑制Raf/MEK/ERK通路的机制基本上依赖于Ras(刺激)和Rap-1(抑制Raf级联)活性的变化。心脏RAS和Rap-1活性明显增强，而ARB仅抑制RAS活性，而不抑制Rap-1活性。RAF免疫沉淀实验证实，经ARB处理后，ISO诱导的MEK的总形式和磷酸化形式的结合增加完全正常化。这些结果可能为AT1受体拮抗剂对交感兴奋性心力衰竭患者心脏重构和功能的有益作用提供了分子基础。较少

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