2. Academic Validation
  3. Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway

Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway

  • Cardiovasc Toxicol. 2023 Mar 19. doi: 10.1007/s12012-023-09789-3.
Gang Zhou 1 2 3,  Hui Wu 4 5 6,  Jian Yang 1 7 2,  Ming Ye 1 2,  Di Liu 1 2,  Yunzhao Li 1 2,  Dong Zhang 1 2,  Jing Zhang 1 2 3,  Qingzhuo Yang 1 2,  Yanfang Liu 1 2
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China.
  • 2 HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China.
  • 3 Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China.
  • 4 Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China. [email protected].
  • 5 Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China. [email protected].
  • 6 HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China. [email protected].
  • 7 Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China.
PMID: 36934206 DOI: 10.1007/s12012-023-09789-3
Abstract

Necroptosis is a crucial programmed cell death that is tightly associated with myocardial ischemia/reperfusion injury (MI/RI). Liraglutide is an effective option for the treatment of type 2 diabetes and has recently been reported to exert cardioprotective effects on MI/RI. Researchers do not know whether the cardioprotective effect of liraglutide is involved in regulating Necroptosis. This study aimed to explore the effect of liraglutide on MI/RI-induced Necroptosis and its potential mechanisms. Hypoxia/reoxygenation (H/R) was performed on H9c2 cells in vitro to simulate ischemia/reperfusion (I/R) injury, and an MI/RI rat model was established in vivo by ligating the anterior descending branch of the left coronary artery. H/R or I/R damage was assessed by performing biochemical assay, Hoechst 33342/PI staining, H&E (hematoxylin and eosin) staining, and Annexin-V/PI staining. Our data revealed that liraglutide resulted in markedly increased cell viability and reduced cardiac Enzyme release by protecting cardiomyocytes from a necrosis-like phenotype after H/R. The myocardial infarct size and cardiac Enzyme release were reduced in the heart tissues from the liraglutide-treated group. The levels of necroptosis-associated proteins (receptor-interacting protein kinase 3 (RIPK3), p-RIPK3, and phosphorylated-mixed lineage kinase domain-like protein (p-MLKL)) were also reduced by the liraglutide treatment. Mechanistically, we revealed that liraglutide exerted cardioprotective effects through a glucagon-like peptide-1 receptor (GLP-1R) and phosphatidylinositol-3 kinase (PI3K)-dependent pathway. Both the GLP-1R inhibitor exendin (9-39) and the PI3K Inhibitor LY294002 abrogated the protective effects of liraglutide in vitro. We found that liraglutide may attenuate MI/RI by inhibiting Necroptosis, in part by enhancing the activity of the GLP-1R/PI3K/Akt pathway.

Keywords

Glucagon-like peptide-1 receptor (GLP-1R); Liraglutide; Myocardial ischemia/reperfusion injury (MI/RI); Necroptosis; PI3K/Akt pathway.

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