Zheng Ming, Zhu Weizhong, Han Qide, Xiao Rui-Ping
Institute of Cardiovascular Sciences, Peking University, Beijing 100083, People's Republic of China.
Pharmacol Ther. 2005 Dec;108(3):257-68. doi: 10.1016/j.pharmthera.2005.04.006. Epub 2005 Jun 24.
The stimulation of beta-adrenergic receptor (betaAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct betaAR subtypes, beta1AR, beta2AR, and beta3AR, are identified in various types of cells. While both beta1AR and beta2AR, the predominant betaAR subtypes expressed in the heart of many mammalian species including human, are coupled to the Gs-adenylyl cyclase-cAMP-PKA pathway, beta2AR dually activates pertussis toxin-sensitive Gi proteins. During acute stimulation, beta2AR-Gi coupling partially inhibits the Gs-mediated positive contractile and relaxant effects via a Gi-Gbetagamma-phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent beta1AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP-PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent beta2AR activation protects myocardium by a cell survival pathway involving Gi, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these betaAR subtypes and discuss how these subtype-specific properties of betaARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain beta-blockers in the treatment of congestive heart failure.
β-肾上腺素能受体（βAR）的刺激在调节正常和衰竭心脏的心肌功能及形态方面起着关键作用。在各种类型的细胞中已鉴定出三种在基因和药理学上不同的βAR亚型，即β1AR、β2AR和β3AR。虽然β1AR和β2AR这两种在包括人类在内的许多哺乳动物心脏中表达的主要βAR亚型都与Gs-腺苷酸环化酶-cAMP-PKA途径偶联，但β2AR还双重激活百日咳毒素敏感的Gi蛋白。在急性刺激期间，β2AR-Gi偶联通过成年啮齿动物心肌细胞中一种依赖Gi-Gβγ-磷酸肌醇3-激酶（PI3K）的机制部分抑制Gs介导的正性收缩和舒张作用。更重要的是，在体内啮齿动物心脏和培养的心肌细胞中，持续的β1AR刺激通过钙调蛋白依赖性蛋白激酶II（CaMKII）而非cAMP-PKA依赖性机制引发多种心脏毒性作用，包括心肌细胞凋亡和肥大。相比之下，持续的β2AR激活通过涉及Gi、PI3K和Akt的细胞存活途径保护心肌。在本综述中，我们试图突出这些βAR亚型的不同功能和信号传导机制，并讨论βAR的这些亚型特异性特性如何可能影响充血性心力衰竭（CHF）的发病机制以及某些β受体阻滞剂在治疗充血性心力衰竭中的治疗效果。
