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
  • 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.
Products