Valsartan mitigates myocardial ischemia-reperfusion injury by inhibiting ferritinophagy-mediated ferroptosis via AT1R/Mst1/Beclin1 axis

Revascularization is crucial for acute myocardial infarction (AMI), but it often leads to myocardial ischemia-reperfusion injury (IRI), which can diminish therapeutic benefits. Current strategies to alleviate IRI are largely insufficient. Recent research highlights cardiomyocyte ferritinophagy as a key driver of myocardial ferroptosis and IRI. Understanding and targeting the specific molecular pathways that regulate ferritinophagy and ferroptosis could offer novel therapeutic avenues to protect the heart during reperfusion.

Researchers investigated valsartan's effects on IRI using hypoxia-reoxygenation (H/R) treated cardiomyocytes and in vivo models. They employed RT-PCR, western blotting, co-immunoprecipitation, and immunofluorescence co-localisation to analyze molecular changes. The study examined the impact of valsartan on Mst1 and Beclin1 phosphorylation, ferritinophagy, and ferroptosis. Control arms included untreated cells/animals, treatment with a ferroptosis inhibitor, and cardiomyocyte-specific Mst1 knockout mice. Additionally, the study included a clinical observation of pre-revascularization administration of valsartan in patients with AMI, registered under TRN ChiCTR2100043501.

Hypoxia-reoxygenation (H/R) in cardiomyocytes induced dephosphorylation of Mst1 at Thr183, which subsequently impaired Beclin1 phosphorylation at Ser295. This cascade potentiated ferritinophagy, triggered ferroptosis, and exacerbated H/R-induced cardiomyocyte injury. Valsartan effectively restored the phosphorylation of Mst1 at Thr183 and Beclin1 at Ser295, thereby inhibiting myocardial ferritinophagy and ferroptosis. Valsartan's inhibitory effect on cardiomyocyte ferritinophagy was also linked to its ability to block the angiotensin II type 1 receptor (AT1R).