1. Selective Inhibition of NLRP3 Inflammasome Reverses Pressure Overload-Induced Pathological Cardiac Remodeling by Attenuating Hypertrophy, Fibrosis, and Inflammation.
- Author
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Zhao M, Zhang J, Xu Y, Liu J, Ye J, Wang Z, Ye D, Feng Y, Xu S, Pan W, Wang M, and Wan J
- Subjects
- Animals, Aorta, Thoracic surgery, Calcineurin metabolism, Cardiomegaly etiology, Cardiomegaly metabolism, Cardiomegaly pathology, Cardiotonic Agents pharmacology, Cardiotonic Agents therapeutic use, Cardiovascular Surgical Procedures adverse effects, Constriction, Pathologic complications, Cytokines genetics, Cytokines metabolism, Disease Models, Animal, Fibrosis metabolism, Fibrosis pathology, Furans pharmacology, Furans therapeutic use, Heart Failure drug therapy, Heart Failure etiology, Heart Failure metabolism, Indenes pharmacology, Indenes therapeutic use, Inflammation metabolism, Ligation, MAP Kinase Signaling System drug effects, Macrophages drug effects, Macrophages metabolism, Male, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Oxidative Stress drug effects, Pressure adverse effects, Sulfonamides pharmacology, Sulfonamides therapeutic use, Mice, Cardiomegaly drug therapy, Fibrosis drug therapy, Inflammasomes antagonists & inhibitors, Inflammation drug therapy, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Ventricular Remodeling drug effects
- Abstract
Activation of the NLRP3 inflammasome promotes pathological cardiac remodeling induced by pressure overload. However, the therapeutic effects of NLRP3 inhibition after cardiac remodeling remain unknown. The present study aimed to investigate whether the selective NLRP3 inhibitor, MCC950, could reverse transverse aortic constriction (TAC)-induced cardiac remodeling. Mice were divided into four groups based on the treatment given: sham, sham + MCC950, TAC, and TAC + MCC950. MCC950 (10 mg/kg, intraperitoneal injection, once per day) was administered from two weeks after TAC or sham surgery for four weeks. Echocardiography, histological analysis, RT-PCR, and Western blotting were performed to explore the function of MCC950 after TAC. We found that MCC950 reversed cardiac dysfunction after TAC. MCC950 attenuated cardiac hypertrophy by down-regulating calcineurin expression and inhibiting MAPK activation. Further, it also alleviated cardiac fibrosis post-TAC by inhibiting the TGF-β/Smad4 pathway, and reduced cardiac inflammation and macrophage infiltration post-TAC, including both M1 and M2 macrophages. Taken together, MCC950 can attenuate cardiac remodeling due to pressure overload by inhibiting hypertrophy, fibrosis, and inflammation. Our study provides a basis for the clinical application of NLRP3 inhibitors in the treatment of non-ischemic heart failure., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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