UBE2D3 contributes to myocardial ischemia-reperfusion injury by regulating autophagy in dependence of p62/SQSTM1 |
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| Institution: | 1. Department of Cardiology, The Second Affiliated Hospital, Kunming Medical University, Kunming 650101, China;2. Department of Anatomy and Histology, School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, China;3. Technology Transfer Center, Kunming Medical University, Kunming 650500, China;1. Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan;2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10463, USA;3. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran;4. Department of Pharmacy, University of Swabi, Pakistan;5. Department of Pharmacy, Abdul Wali Khan University Mardan 23200, Pakistan;1. Department of Thyroid Surgery, Henan Provincial People''s Hospital, Zhengzhou City, Henan Province, China;2. Department of Radiotherapy, Henan Provincial People''s Hospital, Zhengzhou City, Henan Province, China;3. Department of Nephrology, Henan Provincial People''s Hospital, Zhengzhou City, Henan Province, China;1. Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil;2. Postgraduate Program in Pharmacy, Federal University of Santa Catarina, Florianopolis, SC 88040-900, Brazil;1. Laboratory of Animal Anatomy & Tissue Embryology, Department of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China;2. Gansu Province Livestock Embryo Engineering Research Center, Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China |
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| Abstract: | The impairment of autophagic flux has been widely recognized in myocardial ischemia-reperfusion (I/R) injury, but its underlying mechanism contributing to impaired autophagic flux is poorly understood. As celluar major degradation systems, autophagy and ubiquitin proteasome system (UPS) participate in the multitudinous progression of disease by interactive relationship. Especially UBE2D3, one of the ubiquitin-binding enzyme E2 family, is closely related to the regulation impairment of autophagic flux under I/R in our study. Therefore, this study aims to further explore the regulatory mechanism of UBE2D3 in I/R induced autophagy. We determined interference with UBE2D3 alleviated injury of myocardial cells both in vivo and in vitro. Conversely, when inhibiting proteasome function by injecting MG-132, myocardial infarct size of rats became increasingly enhanced, along with the high expression levels of LDH and CK-MB in serum, compared with myocardial I/R injury without treatment of MG-132. This had been caused by UBE2D3 promoting p62/SQSTM1(p62) ubiquitination(Ub), which lead to worsen the impairment of autophagic flux induced by myocardial I/R injury. In addition, UBE2D3 could also participate in the regulation of autophagy by negatively regulating mTOR. But more surprisingly, this mechanism was independent of the known mTOR-beclin1 pathway. These results suggested that in myocardial I/R injury, UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux. Moreover, mTOR was also involved in its regulation of autophagic flux in a way escaped from beclin1. |
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