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      NLRP3 inflammasome, an immune‐inflammatory target in pathogenesis and treatment of cardiovascular diseases

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          Abstract

          Inflammation is an important process involved in several cardiovascular diseases (CVDs), and nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a vital player in innate immunity and inflammation. In this review, we aim to provide a comprehensive summary of the current knowledge on the role and involvement of NLRP3 inflammasome in the pathogenesis and treatment of CVDs. NLRP3 inflammasome functions as a molecular platform, and triggers the activation of caspase‐1 and cleavage of pro‐IL‐1β, pro‐IL‐18, and gasdermin D (GSDMD). Cleaved NT‐GSDMD forms pores in the cell membrane and initiates pyroptosis, inducing cell death and release of many intracellular pro‐inflammatory molecules. NLRP3 inflammasome activation is triggered via inter‐related pathways downstream of K + efflux, lysosomal disruption, and mitochondrial dysfunction. In addition, the Golgi apparatus and noncoding RNAs are gradually being recognized to play important roles in NLRP3 inflammasome activation. Many investigations have revealed the association between NLRP3 inflammasome and CVDs, including atherosclerosis, ischemia/reperfusion (I/R) injury and heart failure induced by pressure overload or cardiomyopathy. Some existing medications, including orthodox and natural medicines, used for CVD treatment have been newly discovered to act via NLRP3 inflammasome. In addition, NLRP3 inflammasome pathway components such as NLRP3, caspase‐1, and IL‐1β may be considered as novel therapeutic targets for CVDs. Thus, NLRP3 inflammasome is a key molecule involved in the pathogenesis of CVDs, and further research focused on development of NLRP3 inflammasome‐based targeted therapies for CVDs and the clinical evaluation of these therapies is essential.

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          Most cited references77

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          Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders

          Jiang et al. identify a selective and direct small-molecule inhibitor for NLRP3 and provide solid evidence showing that NLRP3 can be targeted in vivo to combat inflammasome-driven diseases.
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            Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome

            Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis.
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              Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR-223/NLRP3 axis.

              Atherosclerosis (AS) is an inflammatory disease linked to endothelial dysfunction. Melatonin is reported to possess substantial anti-inflammatory properties, which has proven to be effective in AS. Emerging literature suggests that pyroptosis plays a critical role during AS progression. However, whether pyroptosis contributes to endothelial dysfunction and the underlying molecular mechanisms remained unexploited. This study was designed to investigate the antipyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms. In this study, high-fat diet (HFD)-treated ApoE-/- mice were used as an atherosclerotic animal model. We found intragastric administration of melatonin for 12 weeks markedly reduced the atherosclerotic plaque in aorta. Meanwhile, melatonin also attenuated the expression of pyroptosis-related genes, including NLRP3, ASC, cleaved caspase1, NF-κB/GSDMD, GSDMD N-termini, IL-1β, and IL-18 in aortic endothelium of melatonin-treated animals. Consistent antipyroptotic effects were also observed in ox-LDL-treated human aortic endothelial cells (HAECs). We found that lncRNA MEG3 enhanced pyroptosis in HAECs. Moreover, MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR-223 and to increase NLRP3 expression and enhance endothelial cell pyroptosis. Furthermore, knockdown of miR-223 blocked the antipyroptotic actions of melatonin in ox-LDL-treated HAECs. Together, our results suggest that melatonin prevents endothelial cell pyroptosis via MEG3/miR-223/NLRP3 axis in atherosclerosis, and therefore, melatonin replacement might be considered a new strategy for protecting endothelium against pyroptosis, thereby for the treatment of atherosclerosis associated with pyroptosis.
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                Author and article information

                Contributors
                chen.ruizhen@zs-hospital.sh.cn
                Journal
                Clin Transl Med
                Clin Transl Med
                10.1002/(ISSN)2001-1326
                CTM2
                Clinical and Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2001-1326
                09 April 2020
                Jan-Dec 2020
                : 10
                : 1 ( doiID: 10.1002/ctm2.v10.1 )
                : 91-106
                Affiliations
                [ 1 ] Department of Cardiology Zhongshan Hospital Shanghai Institute of Cardiovascular Diseases Shanghai Medical College of Fudan University Shanghai China
                [ 2 ] Department of General Practice Zhongshan Hospital Shanghai Medical College of Fudan University Shanghai China
                Author notes
                [*] [* ] Correspondence

                Ruizhen Chen, Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, Room 205, 1609 Xietu Road, Shanghai, China.

                Email: chen.ruizhen@ 123456zs-hospital.sh.cn

                Author information
                https://orcid.org/0000-0003-0333-2695
                Article
                CTM213
                10.1002/ctm2.13
                7240865
                32508013
                e3d59b03-6215-4195-b964-2ad7b41056bf
                © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 March 2020
                : 12 March 2020
                Page count
                Figures: 3, Tables: 2, Pages: 16, Words: 9015
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81772109
                Award ID: 81521001
                Award ID: 81671937
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                January/December 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.2 mode:remove_FC converted:21.05.2020

                Medicine
                atherosclerosis,heart failure,inflammation,ischemia/reperfusion injury,nlrp3 inflammasome
                Medicine
                atherosclerosis, heart failure, inflammation, ischemia/reperfusion injury, nlrp3 inflammasome

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