心脏中不同β肾上腺素受体亚型的信号体系及其病理生理意义(英文)  

Distinct p-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance

作　　者：郑铭[1] 韩启德[1] 肖瑞平[1] 

机构地区：[1]北京大学心血管研究所,北京100083

出　　处：《生理学报》2004年第1期1-15,共15页Acta Physiologica Sinica

基　　金：This work was supported by the National Natural Science Foundation of China (No.30100215 and 30225036);Peking University 985 Project and National Basic Research Priorities Programme of China(G2000056906).

摘　　要：生理情况下,β肾上腺素受体(βAR)对心肌收缩和舒张活动起至关重要的作用;病理情况下,长期激动βAR可以诱发心肌细胞肥大、凋亡以及细胞坏死等心肌重塑性活动,从而参与了慢性心衰的发病过程。近十年以来,许多资料表明β1利β2肾上腺素受体亚型(β1AR和β2AR)共存于心脏中,且激动不同信号系统。短时间激动β1AR,使Gs蛋白-腺苷酸环化酶-环苷腺酸-蛋白激酶A(Gs-adenylyl cyclase-cAMP-PKA)信号体系激活并广布于细胞内,而激动β2AR则同时激活Gi蛋白而产生空间及功能局限的cAMP信号;长时间激动β1AR和β2AR则对心肌细胞的命运产生不同影响:β1AR诱导细胞肥大和凋亡,β2AR促使细胞存活。β2AR的心肌保护作用是通过激活Gi蛋白-Gβr-PI3K-Akt途径介导。但出乎意料,β1AR的心肌肥厚和凋亡效应并不依赖于经典的cAMP/PKA信号途径,而是激活钙/钙调素依赖性蛋白激酶Ⅱ(CaMK Ⅱ)途径。用心肌特异性表达βAR亚型的转基因小鼠进行实验,进一步证实不同βAR亚 型在调节心肌重塑和功能方面作用各异。βAR亚型作用不同的新观点不仅为β阻滞剂治疗慢性心衰提供了分子和细胞机制的依据,而且提出了选择性β1AR阻滞和β2AR激动联合治疗慢性心衰的新的治疗思路。In the heart, stimulation of β-adrenergic receptors (βAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a 'fight-or-flight' situation. However, sustained β-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the patho-genesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac βAR subtypes, mainly β1AR and β2AR, activate markedly different signaling cascades. As a result, acute β1AR stimulation activates the Gs-adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas β2AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent Gi activation. Chronic stimulation of β1AR and β2AR elicits opposing effects on the fate of cardiomyocytes: β1AR induces hypertrophy and apoptosis; but β2AR promotes cell survival. The cardiac protective effect of β2AR is mediated by a signaling pathway sequentially involving Gi, Gβγ, PI3K and Akt. Unexpectedly, β1AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca2+/calmodulin-dependent kinase Ⅱ (CaMK Ⅱ). The outcomes of cardiac-specific transgenic overexpression of either βAR subtype in mice have reinforced the fundamentally different functional roles of these βAR subtypes in governing cardiac remodeling and performance. These new insights regarding βAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of PAR blockers in patients with chronic heart failure, but also delineate rationale for combining selective β1AR blockade with moderate β2AR activation as a potential novel therapy for the treatment of chronic heart failure.

关 键 词：Β肾上腺素受体 心脏 信号转导 

分 类 号：R363[医药卫生—病理学]