IL-35 attenuates pressure overload-induced cardiac oxidative stress, inflammation, and heart failure development

Background and Objective: Cardiac oxidative stress and inflammation promote heart failure development. Previous studies showed that interleukin-35 (IL-35) suppresses endothelial oxidative stress, IL-12α expression, and inflammation. However, the effects of IL-35 on cardiac oxidative stress, cardiac inflammation, and heart failure progression are unclear.Methods: C57BL/6J mice were subjected to transverse aortic constriction (TAC) and treated with IL-35 or vehicle. Cardiac oxidative stress, inflammatory responses, and cardiac function, as well as pulmonary inflammation and lung function, were systematically evaluated. In parallel, the impact of IL-12α deficiency on systolic overload–induced cardiac oxidative stress, inflammation, and dysfunction was examined using IL-12α knockout (KO) mice.Results: IL-35 treatment significantly attenuated TAC-induced cardiac dysfunction at early and late stages of heart failure. IL-35 markedly reduced increases in left ventricular (LV) and lung weights and alleviated pathological LV hypertrophy and fibrosis. IL-35 also significantly suppressed TAC-induced cardiac oxidative stress and inflammatory responses. Moreover, we found that IL-12α deficiency also effectively attenuated TAC-induced cardiac oxidative stress, inflammation, and dysfunction.Conclusions: IL-35 exerts protective effects against pressure overload–induced cardiac oxidative stress, inflammation, fibrosis, heart failure, and the consequent pulmonary inflammation and remodeling. These findings demonstrate that IL-35 is an effective therapeutic molecule in attenuating HF development through reducing cardiac oxidative and inflammation.