Carnosic acid protects against mitochondrial dysfunction and ferroptosis in myocardial ischemia/reperfusion injury through mediating Mfn2.

The pathogenesis of myocardial ischemia/reperfusion injury (MIRI) is complicated and involves various factors, including iron overload, oxidative stress, mitochondrial damage, calcium overload, and inflammation. Hence, the aim of this study was to explore the molecular mechanisms of MIRI and verify the myocardial protection mechanism of carnosic acid (CA) in MIRI. In vivo and in vitro MIRI models were established. The results of this study verified that pretreatment with CA effectively increased cell viability, reduced the apoptosis rate and lactate dehydrogenase activity, maintained mitochondrial dynamic balance, and inhibited iron overload and abnormal lipid metabolism in cardiomyocytes with anoxia/reoxygenation treatment. Pretreatment with CA not only improved cardiac function and reduced infarct size in rats treated with ischemia/reperfusion (I/R) but also decreased reactive oxygen species levels and the rate of apoptotic cardiomyocytes in myocardium induced by I/R. These cardioprotective effects of CA could be inhibited by treatment with adenoviral vector expressing Mfn2 short hairpin RNA. In general, CA pretreatment protected cardiomyocytes against MIRI injury by inhibiting ferroptosis and maintaining mitochondrial dynamic homeostasis through an Mfn2-dependent mechanism.