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心脏中不同#beta#肾上腺素受体亚型的信号体系及其病理生理意义

郑铭, 韩启德, 肖瑞平

北京大学心血管研究所.北京 100083

摘要

生理情况下,#beta#肾上腺素受体(#beta#AR)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#beta#AR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#beta#_(1)和#beta#_(2)肾上腺素受体亚型(#beta#_(1)AR和#beta#_(2)AR)共存于心脏中,且激动不同信号系统。短时间激动#beta#_(1)AR使G_(s)蛋白-腺苷酸环化酶-环苷腺酸-蛋白激酶A(G_(s)-adenylyl cyclase-cAM-PKA)信号体系激活并广布于细胞内,而激动#beta#_(2)AR则同时激活G_(i)蛋白而产生空间及功能局限的cAMP信号;长时间激动#beta#_(1)AR和#beta#_(2)AR则对心肌细胞的命运产生不同影响;#beta#_(1)AR诱导细胞肥大和凋亡,#beta#_(2)AR促使细胞存活。#beta#_(2)AR的心肌保护作用是通过激活G_(i)蛋白-G_(#beta##gamma#)-PI3K-Akt途径介导。但出乎意料,#beta#_(1)AR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(CaMKⅡ)途径。用心肌特异性表达#beta#AR亚型的转基因小鼠进行实验,进一步证实不同#beta#AR亚型在调节心肌重塑和功能方面作用各异。#beta#AR亚型作用不同的新观点不仅为#beta#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#beta#_(1)AR阻滞和#beta#_(2)AR激动联合治疗慢性心衰的新的治疗思路。

关键词： β-adrenergic receptors; heart; signal transduction

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

Zheng Ming, Han Qide, Xiao Ruiping

The Institute of Molecular Medicine,Peking University.Beijing 100083

Abstract

As a result, acute #beta#_(1)AR stimulation activates the G_(s)-adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas #beta#_(2)AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent G_(i) activation. Chronic stimulation of #beta#_(1)AR and #beta#_(2)AR elicits opposing effects on the fate of cardiomyocytes: #beta#_(1)AR induces hypertrophy and apoptosis; but #beta#_(2)AR promotes cell survival. The cardiac protective effect of #beta#_(2)AR is mediated by a signaling pathway sequentially involving G_(i), G_(#beta##gamma#), PI3K and Akt. Unexpectedly, #beta#_(1)AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca~(2+)/calmodulin-dependent kinase II (CaMK II). The outcomes of cardiac-specifici transgenic overexpression of either #beta#AR subtype in mice have reinforced the fundamentally different functional roles of these #beta#AR subtypes in governing cardiac remodeling and performance. These new insights regarding #beta#AR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of #beta#AR blockers in patients with chronic heart failure, but also delineate rationale for combining selective #beta#_(1)AR blockade with moderate #beta#_(2)AR activation as a potential novel therapy for the treatment of chronic heart failure.

Key words: β肾上腺素受体;心脏;信号传导

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引用本文：

郑铭, 韩启德, 肖瑞平. 心脏中不同#beta#肾上腺素受体亚型的信号体系及其病理生理意义[J]. 生理学报 2004; 56 (1): .

Zheng Ming, Han Qide, Xiao Ruiping. Distinct #beta#-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance. Acta Physiol Sin 2004; 56 (1): (in Chinese with English abstract).