Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-mediated necroptosis
Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-mediated necroptosis
复制标题
CB2受体的药理激活可防止与RIP1/RIP3/MLKL介导的坏死性凋亡相关的乙醇诱导的心肌损伤
DOI：
10.1007/s11010-020-03828-1
复制
发表时间：
2020-07-17
影响因子：
4.3
通讯作者：
Jiang, Yan
中科院分区：
文献类型：
--
作者：
Liu, Xiaochen;Zhang, Dingang;Jiang, Yan
慢性乙醇滥用可导致心脏的有害后果，导致收缩功能障碍、心率变异性、心律失常和心脏重塑。然而，对乙醇诱导的心肌病的确切分子机制知之甚少。在这方面，本研究的目的是描述RIP 1/RIP 3/MLKL介导的坏死性细胞死亡，可能参与乙醇诱导的心肌病和CBR介导的信号通路和心肌损伤的影响。我们进行了乙醇蒸汽给药实验，以分析乙醇对雄性C57 BL/6 J小鼠心脏结构和功能的影响。乙醇诱导心脏结构和功能显著下降，表现为射血分数和缩短分数下降，血清肌酸激酶水平、心肌胶原蛋白含量和炎症反应增加。此外，乙醇还上调心肌中坏死性凋亡相关标志物如p-RIP 1、p-RIP 3和p-MLKL的表达水平。Nec-1治疗通过挽救心脏组织、改善心功能、减轻炎症和坏死性凋亡而发挥显著的心脏保护作用。此外，乙醇滥用导致内源性大麻素系统失衡，并调节心肌中的两种大麻素受体（CB 1 R和CB 2 R）。用选择性CB 2 R激动剂JWH-133或AM 1241治疗，显著改善心功能不全，并减少乙醇诱导的心肌坏死性凋亡。总之，我们的数据提供的证据表明，乙醇滥用诱导的心脏毒性可能归因于RIP 1/RIP 3/MLKL介导的坏死性凋亡。此外，CB 2 R的药理学激活可能代表了一种新的心脏保护策略，以对抗乙醇诱导的心脏毒性。
Chronic ethanol abuse can lead to harmful consequences for the heart, resulting in systolic dysfunction, variability in the heart rate, arrhythmia, and cardiac remodelling. However, the precise molecular mechanism responsible for ethanol-induced cardiomyopathy is poorly understood. In this regard, the present study aimed to describe the RIP1/RIP3/MLKL-mediated necroptotic cell death that may be involved in ethanol-induced cardiomyopathy and characterize CBR-mediated effects on the signalling pathway and myocardial injury. We performed an ethanol vapour administration experiment to analyse the effects of ethanol on cardiac structure and function in male C57BL/6J mice. Ethanol induced a significant decline in the cardiac structure and function, as evidenced by a decline in ejection fraction and fractional shortening, and an increase in serum Creatine Kinase levels, myocardial collagen content, and inflammatory reaction. Furthermore, ethanol also upregulated the expression levels of necroptosis-related markers such as p-RIP1, p-RIP3, and p-MLKL in the myocardium. Nec-1 treatment exerted significant cardioprotective effects by salvaging the heart tissue, improving the cardiac function, and mitigating inflammation and necroptosis. In addition, ethanol abuse caused an imbalance in the endocannabinoid system and regulated two cannabinoid receptors (CB1R and CB2R) in the myocardium. Treatment with selective CB2R agonists, JWH-133 or AM1241, markedly improved the cardiac dysfunction and reduced the ethanol-induced necroptosis in the myocardium. Altogether, our data provide evidence that ethanol abuse-induced cardiotoxicity can possibly be attributed to the RIP1/RIP3/MLKL-mediated necroptosis. Moreover, pharmacological activation of CB2R may represent a new cardioprotective strategy against ethanol-induced cardiotoxicity.