Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Cardiology, Affiliated Banan Hospital of Chongqing Medical University, Chongqing, China.
Life Sci. 2023 Nov 15;333:122185. doi: 10.1016/j.lfs.2023.122185. Epub 2023 Oct 17.
The purpose of this study was to evaluate the role of the NLRP3-inflammasome in heart failure with preserved ejection fraction (HFpEF).
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 diastolic 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.
Compared with heart failure patients with reduced ejection fraction, patients with HFpEF have significantly elevated serum inflammatory cytokine levels. Serum NLRP3 and interleukin-1β 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-1β 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.
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.
本研究旨在评估 NLRP3 炎性小体在射血分数保留型心力衰竭（HFpEF）中的作用。
检测心力衰竭患者的血清炎性细胞因子。进行相关性分析，以探讨血清炎性细胞因子与左心室舒张功能之间的关系。建立“双打击”（代谢应激和机械应激）HFpEF 小鼠模型。进一步使用 MCC950 确定 NLRP3 炎性小体抑制在 HFpEF 小鼠心脏和肺动脉重构中的作用。
与射血分数降低的心力衰竭患者相比，HFpEF 患者的血清炎性细胞因子水平显著升高。血清 NLRP3 和白细胞介素-1β水平与 HFpEF 的舒张功能呈正相关。在 HFpEF 小鼠模型中，MCC950 抑制 NLRP3 炎性小体可改善运动不耐受、葡萄糖不耐受和左心室舒张功能，但对收缩功能无显著影响。同时，MCC950 减轻了炎性细胞因子的释放、心肌细胞肥大和心脏纤维化。机制上，MCC950 通过抑制 NLRP3-IL-1β 通路的激活和下游炎性细胞因子的级联扩展来发挥潜在的保护作用。此外，MCC950 抑制 NLRP3 炎性小体可降低 HFpEF 中的肺动脉压并改善肺动脉重构。
NLRP3 炎性小体通过激活炎性细胞因子级联反应，在 HFpEF 中的炎症和心脏及肺动脉重构中发挥重要作用。本研究首次全面阐述了 NLRP3 炎性小体在 HFpEF 中的作用，为未来的研究提供了参考。
