FGF21 Blunts Cardiac Ischemia/Reperfusion Injury by Promoting Autophagic Flux Via Stat1/Irgm1 Pathway

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Physiology

Background:

• Myocardial ischemia/reperfusion (I/R) injury is a significant clinical challenge.
• Fibroblast Growth Factor 21 (FGF21) plays a role in metabolic regulation and stress response.
• The specific mechanisms of FGF21 in myocardial I/R injury require further elucidation.

Purpose of the Study:

• To investigate the role of Fibroblast Growth Factor 21 (FGF21) in myocardial ischemia/reperfusion (I/R) injury.
• To identify key molecular pathways regulated by FGF21 during I/R.
• To explore the therapeutic potential of FGF21 in mitigating myocardial I/R injury.

Main Methods:

• Analysis of FGF21 levels in patients and animal models of myocardial I/R.
• Utilizing FGF21 knockout mice and recombinant human FGF21 (rhFGF21) treatment.
• Employing bioinformatics to identify autophagy-related genes.
• Investigating the role of immunity-related GTPase M1 (Irgm1) and the STAT1 pathway.

Main Results:

• FGF21 was upregulated in myocardial I/R injury contexts.
• FGF21 deficiency exacerbated I/R injury, while rhFGF21 administration mitigated it.
• Irgm1 was identified as an autophagy-related gene downregulated in FGF21 knockout I/R hearts.
• rhFGF21 rescued impaired autophagic flux in FGF21 knockout mice via the STAT1 pathway.
• rhFGF21's protective effects were diminished in Irgm1-knockdown cardiomyocytes.

Conclusions:

• FGF21 deficiency intensifies myocardial I/R injury by impairing autophagic flux.
• The FGF21-Irgm1 axis, involving the STAT1 pathway, is crucial for regulating autophagy during I/R.
• Targeting FGF21 or Irgm1 presents a potential therapeutic strategy for myocardial I/R injury.