Yichao Zhao
Jie He
Yang Yan
Longwei Xu
Nan Lin
Qingqi Ji
Renyang Tong
Yanan Fu
Yu Gao
Yuanyuan Su
Ancai Yuan
Ben He
Jun Pu
Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
More InformationCorresponding author: E-mail address: heben1025@hotmail.com (Ben He);E-mail address: pujun310@hotmail.com (Jun Pu)
Received Date: 2017-06-30
Accepted Date:2017-12-27
Rev Recd Date:2017-12-26
Available Online: 2017-12-29 Publish Date:2018-03-20
Abstract
Abstract
Sentrin-specific protease 3 (SENP3), a member of the desumoylating enzyme family, is known as a redox sensor and could regulate multiple cellular signaling pathways. However, its implication in myocardial ischemia reperfusion (MIR) injury is unclear. Here, we observed that SENP3 was expressed and upregulated in the mouse heart depending on reactive oxygen species (ROS) production in response to MIR injury. By utilizing siRNA-mediated cardiac specific gene silencing, SENP3 knockdown was demonstrated to significantly reduce MIR-induced infarct size and improve cardiac function. Mechanistic studies indicated that SENP3 silencing ameliorated myocardial apoptosis mainly via suppression of endoplasmic reticulum (ER) stress and mitochondrial-mediated apoptosis pathways. By contrast, adenovirus-mediated cardiac SENP3 overexpression significantly exaggerated MIR injury. Further molecular analysis revealed that SENP3 promoted mitochondrial translocation of dynamin-related protein 1 (Drp1) in reperfused myocardium. In addition, mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, significantly attenuated the exaggerated mitochondrial abnormality and cardiac injury by SENP3 overexpression after MIR injury. Taken together, we provide the first direct evidence that SENP3 upregulation pivotally contributes to MIR injury in a Drp1-dependent manner, and suggest that SENP3 suppression may hold therapeutic promise for constraining MIR injury.Keywords: Heart,
Ischemia reperfusion,
SUMOylation,
Sentrin-specific protease
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