NLRP3-inflammasome inhibition by MCC950 attenuates cardiac and pulmonary artery remodelling in heart failure with preserved ejection fraction

Aims: The purpose of this study was to evaluate the role of the NLRP3-inflammasome in heart failure with preserved ejection fraction (HFpEF).Main methods: Serum inflammatory cytokines were detected in patients with heart failure. Correlation analysis was performed to investigate the relationship between serum inflammatory cytokines and left ventricular dia-stolic function. A 'two-hit' (metabolic stress and mechanical stress) mouse model of HFpEF was established. Furthermore, MCC950 was used to determine the role of NLRP3-inflammasome inhibition in cardiac and pulmonary artery remodelling in HFpEF mice.Key findings: Compared with heart failure patients with reduced ejection fraction, patients with HFpEF have significantly elevated serum inflammatory cytokine levels. Serum NLRP3 and interleukin-113 levels were positively correlated with the diastolic function of HFpEF. In the HFpEF mouse model, the inhibition of the NLRP3-inflammasome by MCC950 improved exercise intolerance, glucose intolerance, and left ventricular diastolic function, but had no significant effect on systolic function. Meanwhile, MCC950 attenuated the release of inflammatory cytokines, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, the potential protective effects of MCC950 are achieved by inhibiting activation of the NLRP3-IL-113 pathway and cascade expansion of downstream inflammatory cytokines. Additionally, the inhibition of NLRP3-inflammasome by MCC950 reduced pulmonary artery pressure and improved pulmonary artery remodelling in HFpEF.Significance: The NLRP3-inflammasome plays a considerable role in inflammation and cardiac and pulmonary artery remodelling in HFpEF by activating the cascade reaction of inflammatory cytokines. This study is the first to comprehensively elucidate the role of the NLRP3-inflammasome in HFpEF, and will provide reference for future study.