Irisin alleviates myocardial ischemia-reperfusion injury by inhibiting ferroptosis

  AIM  To investigate whether Irisin protects against myocardial ischemia/reperfusion (MI/R) induced ferroptosis in mice.

  METHODS  Eighty healthy male C57 mice aged 5 weeks were randomly divided into a normal control group (40 mice) and an exercise training group (40 mice). After the exercise training, the two groups of mice were further divided into sham group and MI/R group (20 in each group). The in vivo mouse models of myocardial I/R injury were used. After 30 min ischemia and 24 h reperfusion period, heart tissues were excised. The levels of irisin in serum and tissues of each group, the expression of iron death-related signals, and the area of myocardial infarction were measured. Myocardial function was also evaluated. In cytology experiments, in vitro hypoxia/reoxygenation (H/R) injury model for H9C2 cardiomyocytes with irisin treatment were used to detect the expression of ferroptosis-related signals.

  RESULTS  The ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly reduced the MI/R myocardial infarction area and decreased the levels of cardiac Ptgs2 mRNA and MDA, suggesting that myocardial ferroptosis was involved in MI/R injury. Compared with the control group, aerobic exercise training effectively increased the level of irisin in skeletal muscle and myocardium (P<0.05). In addition, the degree of myocardial ferroptosis in the exercise MI/R group was significantly inhibited, manifested as myocardial Ptgs2mRNA, MDA and lipid peroxidation were significantly reduced (P<0.05), while cardiac function was significantly improved (P<0.05). Exogenous supplementation of irisin effectively increased the level of GPX4 in MI/R myocardium, inhibited myocardial ferroptosis, and reduced the area of myocardial infarction (P<0.05). Cytological experiments found that irisin-induced ferroptosis inhibition was effectively blocked by knockdown of integrin αV/β5 receptor using siRNA.

  CONCLUSION  Irisin inhibits MI/R myocardial ferroptosis through the integrin αV/β5 -GPX4 signaling pathway. Aerobic exercise training achieves cardioprotection by increasing the level of endogenous irisin.