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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。
Under physiological conditions, β-adrenergic receptor (βAR) plays an important role in myocardial contractile and diastolic activity; long-term agonistic βAR can induce cardiomyocyte hypertrophy, apoptosis and necrosis of myocardial remodeling activities under pathological conditions, Thus participating in the pathogenesis of chronic heart failure. In the last decade, many data indicate that beta 1-adrenergic receptor subtypes (β1AR and β2AR) coexist in the heart and activate different signaling systems. In a short time, β1AR was activated to activate Gs-adenylyl cyclase-cAMP-PKA signal system and widely distributed in cells, while activation of β2AR was activated Gi protein and produce spatial and functional limitations of cAMP signal; prolonged agonistic β1AR and β2AR have a different impact on the fate of cardiomyocytes: β1AR induced cell hypertrophy and apoptosis, β2AR promote cell survival. Myocardial protection of β2AR is mediated through activation of the Gi-Gβr-PI3K-Akt pathway. Surprisingly, the cardiac hypertrophy and apoptosis effects of β1AR did not depend on the classical cAMP / PKA signaling pathway but activated the CaMKII pathway. Experiments with cardiac-specific transgenic mice expressing the [beta] AR subtype further confirm that different [beta] AR subtypes have different roles in regulating myocardial remodeling and function. The new idea that βAR subtypes play different roles not only provides molecular and cellular basis for the treatment of chronic heart failure with β-blocker, but also presents a new therapeutic approach for the treatment of chronic heart failure with selective β1AR blockade and β2AR agonism.