Interleukin 35 ameliorates myocardial ischemia‐reperfusion injury by activating the gp130‐STAT3 axis

Abstract Myocardial ischemia‐reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL‐35) exhibits anti‐inflammatory properties via the engagement of the gp130, IL‐12Rβ2 and IL‐27Rα receptors. However, whether IL‐35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL‐35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL‐35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL‐35‐mediated protective effect on MIRI using cardiomyocyte‐specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio‐protection induced by IL‐35. Interestingly, IL‐35 induced gp130 homodimer and gp130/IL‐12Rβ2 heterodimers in cardiomyocyte. Our results indicate that IL‐35 can execute a protective role against MIRI through a novel signaling pathway, IL‐35‐gp130‐STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.