Frontiers in Cardiovascular Medicine (May 2022)

MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice

  • Menglong Wang,
  • Menglong Wang,
  • Menglong Wang,
  • Mengmeng Zhao,
  • Mengmeng Zhao,
  • Mengmeng Zhao,
  • Junping Yu,
  • Junping Yu,
  • Junping Yu,
  • Yao Xu,
  • Yao Xu,
  • Yao Xu,
  • Jishou Zhang,
  • Jishou Zhang,
  • Jishou Zhang,
  • Jianfang Liu,
  • Jianfang Liu,
  • Jianfang Liu,
  • Zihui Zheng,
  • Zihui Zheng,
  • Zihui Zheng,
  • Jing Ye,
  • Jing Ye,
  • Jing Ye,
  • Zhen Wang,
  • Zhen Wang,
  • Zhen Wang,
  • Di Ye,
  • Di Ye,
  • Di Ye,
  • Yongqi Feng,
  • Yongqi Feng,
  • Yongqi Feng,
  • Shuwan Xu,
  • Shuwan Xu,
  • Shuwan Xu,
  • Wei Pan,
  • Wei Pan,
  • Wei Pan,
  • Cheng Wei,
  • Cheng Wei,
  • Cheng Wei,
  • Jun Wan,
  • Jun Wan,
  • Jun Wan

DOI
https://doi.org/10.3389/fcvm.2022.727474
Journal volume & issue
Vol. 9

Abstract

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Obesity is often accompanied by hypertension. Although a large number of studies have confirmed that NLRP3 inhibitors can improve cardiac remodeling in mice with a normal diet, it is still unclear whether NLRP3 inhibitors can improve heart failure (HF) induced by pressure overload in obese mice. The purpose of this study was to explore the role of MCC950, a selective NLRP3 inhibitor, on HF in obese mice and its metabolic mechanism. Obese mice induced with a 10-week high-fat diet (HFD) were used in this study. After 4 weeks of HFD, transverse aortic constriction (TAC) surgery was performed to induce a HF model. MCC950 (10 mg/kg, once/day) was injected intraperitoneally from 2 weeks after TAC and continued for 4 weeks. After echocardiography examination, we harvested left ventricle tissues and performed molecular experiments. The results suggest that in obese mice, MCC950 can significantly improve cardiac hypertrophy and fibrosis caused by pressure overload. MCC950 ameliorated cardiac inflammation after TAC surgery and promoted M2 macrophage infiltration in the cardiac tissue. MCC950 not only restored fatty acid uptake and utilization by regulating the expression of CD36 and CPT1β but also reduced glucose uptake and oxidation via regulating the expression of GLUT4 and p-PDH. In addition, MCC950 affected the phosphorylation of AKT and AMPK in obese mice with HF. In summary, MCC950 can alleviate HF induced by pressure overload in obese mice via improving cardiac metabolism, providing a basis for the clinical application of NLRP3 inhibitors in obese patients with HF.

Keywords