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MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133382/ https://www.ncbi.nlm.nih.gov/pubmed/35647084 http://dx.doi.org/10.3389/fcvm.2022.727474 |
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author | Wang, Menglong Zhao, Mengmeng Yu, Junping Xu, Yao Zhang, Jishou Liu, Jianfang Zheng, Zihui Ye, Jing Wang, Zhen Ye, Di Feng, Yongqi Xu, Shuwan Pan, Wei Wei, Cheng Wan, Jun |
author_facet | Wang, Menglong Zhao, Mengmeng Yu, Junping Xu, Yao Zhang, Jishou Liu, Jianfang Zheng, Zihui Ye, Jing Wang, Zhen Ye, Di Feng, Yongqi Xu, Shuwan Pan, Wei Wei, Cheng Wan, Jun |
author_sort | Wang, Menglong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9133382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91333822022-05-27 MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice Wang, Menglong Zhao, Mengmeng Yu, Junping Xu, Yao Zhang, Jishou Liu, Jianfang Zheng, Zihui Ye, Jing Wang, Zhen Ye, Di Feng, Yongqi Xu, Shuwan Pan, Wei Wei, Cheng Wan, Jun Front Cardiovasc Med Cardiovascular Medicine 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. Frontiers Media S.A. 2022-05-12 /pmc/articles/PMC9133382/ /pubmed/35647084 http://dx.doi.org/10.3389/fcvm.2022.727474 Text en Copyright © 2022 Wang, Zhao, Yu, Xu, Zhang, Liu, Zheng, Ye, Wang, Ye, Feng, Xu, Pan, Wei and Wan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cardiovascular Medicine Wang, Menglong Zhao, Mengmeng Yu, Junping Xu, Yao Zhang, Jishou Liu, Jianfang Zheng, Zihui Ye, Jing Wang, Zhen Ye, Di Feng, Yongqi Xu, Shuwan Pan, Wei Wei, Cheng Wan, Jun MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice |
title | MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice |
title_full | MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice |
title_fullStr | MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice |
title_full_unstemmed | MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice |
title_short | MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice |
title_sort | mcc950, a selective nlrp3 inhibitor, attenuates adverse cardiac remodeling following heart failure through improving the cardiometabolic dysfunction in obese mice |
topic | Cardiovascular Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133382/ https://www.ncbi.nlm.nih.gov/pubmed/35647084 http://dx.doi.org/10.3389/fcvm.2022.727474 |
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