SH2B1 protects cardiomyocytes from ischemia/reperfusion injury via the activation of the PI3K/AKT pathway.

Guo Xin, Li Xu-Yong, Hu Shan, Wu Gang, Chen Zhen, Liu Ji-Jun, Ye Ping, Chen Man-Hua

International immunopharmacology 2020 Jun

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Apoptosis, reactive oxidative stress (ROS) and inflammation act as the pivotal pathogenesis of myocardial ischemia/reperfusion (I/R) injury (MIRI). Our prior study and other investigation have demonstrated the participations of src homology 2 (SH2) B adaptor protein 1 (SH2B1) in ischemic injury and cardiac hypertrophy; whereas, the involvements of SH2B1 in MIRI and underlying mechanisms are completely unknown. In present study, MIRI model in vivo was induced by 30 min of ligation of LAD coronary artery and 24 h of reperfusion, and primary cultured cardiomyocytes were challenged with 2 h of hypoxia followed by 4 h of reoxygenation (H/R) to mimic MIRI in vitro. Adenovirus encoding for SH2B1 or GFP were pre-transfected into myocardium prior to MIRI both in vivo and in vitro. The myocardial damage, cardiac function, apoptosis, ROS and inflammation were evaluated systematically. Immunofluorescence staining and western blotting were alternatively performed to detect protein expression. The results exhibited that H/R or I/R significantly reduced SH2B1 in cardiomyocytes, followed by impaired cell survival and function, which were strongly reversed after the adenovirus-mediated SH2B1 up-regulation. Meanwhile, I/R- and H/R-elevated inflammation, apoptosis and ROS were also alleviated by SH2B1 up-regulation. A mechanistic study suggested that the protective contributions of SH2B1 on H/R-suffered cardiomyocytes were based on the activation of the PI3K/AKT pathway. The abolishment of the PI3K/AKT via a pharmacological inhibitor (LY294002) repressed anti-H/R capabilities of SH2B1. Therefore, SH2B1 prevents cardiomyocytes from inflammation, apoptosis and ROS in MIRI partially through the PI3K/AKT-dependent avenues. It may provide a novel therapeutic target for the treatment of MIRI. Copyright © 2019. Published by Elsevier B.V.

Citation

Guo Xin, Li Xu-Yong, Hu Shan, Wu Gang, Chen Zhen, Liu Ji-Jun, Ye Ping, Chen Man-Hua. SH2B1 protects cardiomyocytes from ischemia/reperfusion injury via the activation of the PI3K/AKT pathway. International immunopharmacology. 2020 Jun;83:105910