beta-arrestin 2 mediates cardiac ischemia-reperfusion injury via inhibiting GPCR-independent cell survival signalling
beta-arrestin 2 mediates cardiac ischemia-reperfusion injury via inhibiting GPCR-independent cell survival signalling
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beta-arrestin 2 通过抑制不依赖 GPCR 的细胞存活信号传导介导心脏缺血再灌注损伤
DOI：
10.1093/cvr/cvx147
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发表时间：
2017
影响因子：
10.8
通讯作者：
Zhang Yan
中科院分区：
文献类型：
--
作者：
Wang Yimei;Jin Li;Song Ying;Zhang Mao;Shan Dan;Liu Yuli;Fang Meng;Lv Fengxiang;Xiao Rui-Ping;Zhang Yan
目的缺血性心脏病是世界范围内发病率和死亡率的主要原因。虽然及时恢复冠脉血流(再灌注)是治疗心肌梗死最有效的方法，但再灌注会造成进一步的心脏损伤，即缺血再灌注(I/R)损伤。阻滞素(β-arrestins，Arrbs)传统上被定义为G蛋白偶联受体信号的负性调节因子，但最近的研究表明，它们对于G蛋白非依赖性的、G蛋白偶联受体介导的有偏见的信号转导是必不可少的。有报道称，一些配体通过Arrbs依赖途径具有心脏保护作用。然而，目前尚不清楚Arrbs是否在心脏发挥不依赖受体的生理或病理功能。方法和结果β-arrestin 2(Arrb2)在大鼠心肌I/R损伤后表达上调，而β-arrestin 1(Arrb1)表达上调。培养的新生大鼠心肌细胞Arrb2缺乏可减轻H/R引起的心肌细胞死亡，Arrb2−/−小鼠对I/R损伤所致的心肌损伤具有抵抗作用。相反，Arrb2的上调会触发心肌细胞死亡，并夸大I/R(或H/R)诱导的有害影响。Arrb2通过与PI3K的P85亚基相互作用，负性调节P85-PI3K/CaV3生存复合体的形成，从而阻断PI3K-Akt-GSK3β细胞生存信号通路的激活，从而诱导心肌细胞死亡。结论Arrb2上调是心肌I/R损伤的致病因素，揭示了Arrb2介导的细胞死亡信号通路不依赖于GPCRs的新机制。
AimsIschemic heart disease is a leading cause of morbidity and mortality worldwide. Although timely restoration of coronary blood flow (reperfusion) is the most effective therapeutics of myocardial infarction, reperfusion causes further cardiac damage, i.e. ischemia-reperfusion (I/R) injury. β-arrestins (Arrbs) have been traditionally defined as negative regulators of G protein-coupled receptor (GPCR) signalling, but recent studies have shown that they are essential for G protein-independent, GPCR-mediated biased signalling. Several ligands have been reported to be cardioprotective via Arrbs dependent pathway. However, it is unclear whether Arrbs exert receptor-independent physiological or pathological functions in the heart. Here, we sought to determine whether and how Arrbs play a role in regulating cardiomyocyte viability and myocardial remodelling following I/R injury.Methods and resultsThe expression of β-arrestin 2 (Arrb2), but not β-arrestin 1 (Arrb1), is upregulated in rat hearts subjected to I/R injury, or in cultured neonatal rat cardiomyocytes treated with hypoxia-reoxygenation (H/R) injury. Deficiency of Arrb2 in cultured neonatal rat cardiomyocytes alleviates H/R-induced cardiomyocyte death andArrb2−/− mice are resistant to myocardial damage caused by I/R injury. In contrast, upregulation of Arrb2 triggers cardiomyocyte death and exaggerates I/R (or H/R)-induced detrimental effects. Mechanically, Arrb2 induces cardiomyocyte death by interacting with the p85 subunit of PI3K, and negatively regulating the formation of p85-PI3K/CaV3 survival complex, thus blocking activation of PI3K-Akt-GSK3β cell survival signalling pathway.ConclusionWe define an upregulation of Arrb2 as a pathogenic factor in cardiac I/R injury, and also reveal a novel GPCR-independent mechanism of Arrb2-mediated cell death signalling in the heart.