Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-
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Pharmacological activation of CB2 receptor protects against ethanol‑induced myocardial injury related to RIP1/RIP3/ MLKL‑mediated necroptosis Xiaochen Liu1 · Dingang Zhang1 · Xiaoru Dong1 · Rongzhe Zhu1 · Yonghong Ye1 · Liliang Li1 · Yan Jiang1 Received: 18 February 2020 / Accepted: 7 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Ethanol · Myocardial injury · Necroptosis · Cannabinoid 2 receptor
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11010-020-03828-1) contains supplementary material, which is available to authorized users.
Ethanol abuse has brought serious trouble and economic burden to the whole society. In 2016, about 3 million people died because of harmful use of ethanol, accounting for 5.3% of the total number of deaths worldwide [1]. Studies
* Yan Jiang [email protected]
Yonghong Ye [email protected]
Xiaochen Liu [email protected]
Liliang Li [email protected]
Dingang Zhang [email protected]
1
Xiaoru Dong [email protected]
Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui
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