Abstract

Background Activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome contributes to heart failure (HF) pathogenesis. However, the effect of NLRP3 inhibition on β-adrenergic receptor agonist-induced HF remains unknown. Here, we evaluated the role of MCC950, a selective NLRP3 inhibitor, in isoproterenol (ISO)-induced cardiac dysfunction. Methods Mice were administered ISO (30 mg/kg/day) for 14 days with or without MCC950 (10 mg/kg) injection every other day. Cardiac function and the extent of hypertrophy and fibrosis were measured by echocardiography, HE and Masson trichrome staining, respectively. Immunohistochemistry, quantitative real-time PCR and Western blotting were performed to investigate the impact of MCC950 on ISO-induced cardiac dysfunction. The levels of oxidative stress and cell senescence were detected in H9C2 cells to explore the mechanism of MCC950 on ISO-induced myocardial injury in vitro . Results We found that the NLRP3 inflammasome was significantly activated in response to ISO treatment in mice. Selective inhibition of the NLRP3 inflammasome by MCC950 ameliorated cardiac fibrosis, hypertrophy and inflammation in ISO-treated mice, ultimately improving heart function. Furthermore, MCC950 significantly inhibited ISO-induced oxidative stress in the myocardium, accompanied by increased superoxide dismutase 2 (SOD2) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein. In addition, MCC950 attenuated cardiomyocyte death and senescence in ISO-treated H9C2 cells, which was attributed to the decreased oxidative stress. Conclusion NLRP3 inhibition by MCC950 ameliorated ISO-induced cardiac dysfunction by inhibiting cardiomyocyte senescence and oxidative stress. Therefore, inhibition of the NLRP3 inflammasome may be a potential therapeutic strategy for preventing cardiac dysfunction, especially age-related HF.