Activation of the Macrophage-Associated Inflammasome Exacerbates Myocardial Fibrosis Through the 15-HETE-Mediated Pathway in Acute Myocardial Infarction

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外文摘要：This investigation elucidates the spatiotemporal dynamics of NOD-like receptor family pyrin domain con-taining 3(NLRP3)inflammasome activation following myocardial infarction(MI),a process that has not been fully characterized.We revealed early activation of the NLRP3 inflammasome in mice with MI and characterized its dynamic temporal expression.Notably,the knockout and inhibition of Nlrp3 expression were found to significantly mitigate infarct size and enhance cardiac function.Furthermore,our analysis of the spatial characteristics of inflammasome activation revealed predominant activation in macro-phages and subsequent activation in fibroblasts on the third day post-MI.To elucidate the nexus between macrophage-associated NLRP3 inflammasome activation and myocardial fibrosis,we employed targeted metabolomics analyses of inflammatory oxylipins,small interfering RNA(siRNA)interference experi-ments,and various molecular assays.These findings revealed that macrophage-associated inflammasome activation facilitates the conversion of fibroblasts into myofibroblasts via the 15-hydroxy-5,8,11,13-eicosatetraenoic acid(15-HETE)-mediated small mother against decapentaplegic(Smad)pathway.Additionally,both mass spectrometry imaging(MSI)and targeted metabolomics analyses confirmed the significant increase in 15-HETE levels in mice with MI and in patients with MI and acute coronary syndrome(ACS).Our comprehensive dataset suggests that NLRP3 inflammasome activation in MI is char-acterized by distinct temporal and spatial patterns.These insights mark a significant advancement toward precise MI prevention and treatment strategies,particularly early myocardial fibrosis intervention.

外文关键词：

Myocardial infarctionMacrophage inflammasomeNOD-like receptor family pyrin domaincontaining 3Myocardial fibrosis

作者：

Xu Chen、Zhiyong Du、Dongqing Guo、Jincheng Guo、Qianbin Sun、Tiantian Liu、Kun Hua、Chun Li、Yong Wang、Wei Wang

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作者单位：

School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China

Department of Pharmacy,Air Force Medical Center,Air Force Medical University,Beijing 100142,China

National Clinical Research Center for Cardiovascular Diseases,Beijing Institute of Heart Lung and Blood Vessel Disease,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China

School of Life Sciences,Beijing University of Chinese Medicine,Beijing 100029,China

Modern Research Center for Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China

State Key Laboratory of Traditional Chinese Medicine Syndrome,Guangzhou University of Chinese Medicine,Guangzhou 510006,China

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出版年：

2024

DOI：

10.1016/j.eng.2024.05.015

工程(英文)

CSTPCDEI

ISSN：2095-8099

年,卷(期)：2024.42(11)