2. Academic Validation
  3. Exendin-4 alleviates myocardial ischemia reperfusion injury by enhancing autophagy through promoting nuclear translocation of TFEB

Exendin-4 alleviates myocardial ischemia reperfusion injury by enhancing autophagy through promoting nuclear translocation of TFEB

  • Exp Cell Res. 2023 Jan 7;113469. doi: 10.1016/j.yexcr.2023.113469.
Weibin He 1,  Guang Tong 2,  Hualin Fan 3,  Cien Zhen 3,  Lin Zeng 1,  Ling Xue 1,  Jiyan Chen 1,  Zhongchan Sun 4,  Pengcheng He 5
Affiliations

Affiliations

  • 1 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China; Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China.
  • 2 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China; Department of Cardiac Surgery, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China.
  • 3 Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China; Department of Cardiology, School of Medicine, South China University of Technology, 510006 Guangzhou, China.
  • 4 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China; Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China. Electronic address: sunzhongchan@gdph.org.cn.
  • 5 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China; Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China; Department of Cardiology, Heyuan People's Hospital, 517000 Heyuan, China. Electronic address: gdhpc100@126.com.
PMID: 36627100 DOI: 10.1016/j.yexcr.2023.113469
Abstract

Ischemia-reperfusion (I/R) injury (IRI) is a common clinical consequence of myocardial infarction. Exendin-4 is a glucagon-like peptide-1 (GLP-1) analog that has been demonstrated to alleviate myocardial IRI. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in myocardial IRI. However, whether exendin-4 exerts a protective effect on myocardial IRI by modulating Autophagy remains elusive. Herein, we investigated the effect of exendin-4 on autophagic flux and explored the underlying molecular mechanisms. Our data revealed that the autophagic flux was blocked in the human ventricular cardiomyocyte cell lines (AC16) subjected to oxygenation glucose derivation/reoxygenation (OGD/R) in vitro. Exendin-4 pre-treatment markedly restored the blocked autophagic flux induced by OGD/R through promoting nuclear translocation of TFEB and transcription of genes involving Autophagy initiation, the effect of which was reversed by TFEB knockdown. The restoration of autophagic flux contributed to multiple beneficial effects of exendin-4 in cardiomyocytes, including reduction of oxidative stress, preservation of mitochondrial network as well as inhibition of cytochrome c leakage from mitochondrial permeability transition pore (MPTP) and the resulting Apoptosis. Moreover, the administration of exendin-4 reduced infarct size and preserved cardiac function through its anti-apoptosis and antioxidative effects in vivo. These results shed some light on understanding the novel mechanism of exendin-4 as a protective agent against myocardial IRI.

Keywords

Autophagy; Exendin-4; Ischemia reperfusion injury; TFEB.

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