State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Cardiovasc Res. 2017 Nov 1;113(13):1615-1626. doi: 10.1093/cvr/cvx147.
Ischemic 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.
The 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 and Arrb2-/- 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.
We 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.
缺血性心脏病是全球发病率和死亡率的主要原因。尽管及时恢复冠状动脉血流（再灌注）是心肌梗死最有效的治疗方法，但再灌注会导致进一步的心脏损伤，即缺血再灌注（I/R）损伤。β-arrestin（Arrbs）传统上被定义为 G 蛋白偶联受体（GPCR）信号的负调节剂，但最近的研究表明，它们对于 G 蛋白非依赖性、GPCR 介导的偏置信号转导是必不可少的。已经报道了几种配体通过 Arrbs 依赖性途径具有心脏保护作用。然而，Arrbs 是否在心脏中发挥受体独立的生理或病理功能尚不清楚。在这里，我们试图确定 Arrbs 是否以及如何在 I/R 损伤后调节心肌细胞活力和心肌重构。
在经受 I/R 损伤的大鼠心脏或在接受缺氧-复氧（H/R）损伤处理的培养的新生大鼠心肌细胞中，β-arrestin 2（Arrb2）的表达上调，而β-arrestin 1（Arrb1）的表达则没有上调。在培养的新生大鼠心肌细胞中，Arrb2 缺乏可减轻 H/R 诱导的心肌细胞死亡，并且 Arrb2-/- 小鼠对 I/R 损伤引起的心肌损伤具有抗性。相反，Arrbs 的上调会引发心肌细胞死亡，并夸大 I/R（或 H/R）诱导的有害作用。在机制上，Arrb2 通过与 PI3K 的 p85 亚基相互作用诱导心肌细胞死亡，并负调控 p85-PI3K/CaV3 存活复合物的形成，从而阻断 PI3K-Akt-GSK3β 细胞存活信号通路的激活。
我们将 Arrbs 的上调定义为心脏 I/R 损伤的致病因素，并揭示了 Arrbs 介导的心脏细胞死亡信号转导的一种新的 GPCR 非依赖性机制。
