IGFBP2 plays a key role in aerobic exercise-mediated inhibition of ferroptosis in cardiac ischemia/reperfusion (I/R) injury.

BACKGROUND: Ferroptosis is an important mechanism underlying cardiac ischemia/reperfusion (I/R) injury. However, the specific molecular mechanisms by which aerobic exercise alleviates cardiac I/R injury and inhibits ferroptosis remain unclear. METHODS: In this study, we investigated the effects of IGFBP2 on aerobic exercise-mediated protection of cardiac function following I/R and its influence on ferroptosis in cardiomyocytes and SIRT1 activation. Wild-type (WT) or IGFBP2 knockout (IGFBP2_KO) C57BL/6J mice with I/R injury were subjected to aerobic exercise intervention, and cardiomyocytes exposed to hypoxia/reoxygenation (H/R) were treated with IGFBP2. We explored the role of IGF-1R in IGFBP2-mediated cardiac protection using IGF-1R conditional knockout (IGF-1R_CKO) mice subjected to aerobic exercise intervention and cardiomyocytes exposed to H/R and incubated with IGFBP2 and IGF-1R silenced via adenoviral vector (ADV) transfection. The effects of SIRT1 and TXNIP/TRX on ferroptosis in cardiomyocytes exposed to H/R were also examined using SIRT1 inhibitors, SIRT1 agonists, and adenovirus transfection to modulate TXNIP expression levels. RESULTS: Aerobic exercise increased circulating IGFBP2 levels in mice, inhibited ferroptosis in cardiomyocytes, and protected cardiac function following I/R (p < 0.001). IGFBP2 suppressed ferroptosis in cardiomyocytes subjected to H/R and enhanced SIRT1 activation (p < 0.001). IGF-1R_CKO abrogated the inhibitory effects of IGFBP2 and aerobic exercise on cardiomyocyte ferroptosis (p < 0.001). SIRT1 activation inhibited ferroptosis in cardiomyocytes exposed to H/R by downregulating TXNIP expression, upregulating TRX expression, and increasing TXNIP/TRX binding (p < 0.001). Inhibition of TXNIP suppressed ferroptosis following H/R (p < 0.001). CONCLUSION: Aerobic exercise-induced circulating IGFBP2 directly interacts with IGF-1R, leading to increased activation of SIRT1 and reduced levels of free TXNIP, thus inhibiting cardiomyocyte ferroptosis in cardiac I/R injury.