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      Reduced Immunity Regulator MAVS Contributes to Non-Hypertrophic Cardiac Dysfunction by Disturbing Energy Metabolism and Mitochondrial Homeostasis

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          Abstract

          Cardiac dysfunction is manifested as decline of cardiac systolic function, and multiple cardiovascular diseases (CVDs) can develop cardiac insufficiency. Mitochondrial antiviral signaling (MAVS) is known as an innate immune regulator involved in viral infectious diseases and autoimmune diseases, whereas its role in the heart remains obscure. The alteration of MAVS was analyzed in animal models with non-hypertrophic and hypertrophic cardiac dysfunction. Then, MAVS-deficient mice were generated to examine the heart function, mitochondrial status and energy metabolism. In vitro, CRISPR/Cas9-based gene editing was used to delete MAVS in H9C2 cell lines and the phenotypes of mitochondria and energy metabolism were evaluated. Here we observed reduced MAVS expression in cardiac tissue from several non-hypertrophic cardiac dysfunction models, contrasting to the enhanced MAVS in hypertrophic heart. Furthermore, we examined the heart function in mice with partial or total MAVS deficiency and found spontaneously developed cardiac pump dysfunction and cardiac dilation as assessed by echocardiography parameters. Metabonomic results suggested MAVS deletion probably promoted cardiac dysfunction by disturbing energy metabolism, especially lipid metabolism. Disordered and mitochondrial homeostasis induced by mitochondrial oxidative stress and mitophagy impairment also advanced the progression of cardiac dysfunction of mice without MAVS. Knockout of MAVS using CRISPR/Cas9 in cardiomyocytes damaged mitochondrial structure and function, as well as increased mitochondrial ROS production. Therefore, reduced MAVS contributed to the pathogenesis of non-hypertrophic cardiac dysfunction, which reveals a link between a key regulator of immunity (MAVS) and heart function.

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          Most cited references44

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          Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

          In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.
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            Myocardial fatty acid metabolism in health and disease.

            There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the beta-oxidation of long-chain fatty acids. The control of fatty acid beta-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via beta-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid beta-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid beta-oxidation and how alterations in fatty acid beta-oxidation can contribute to heart disease. The implications of inhibiting fatty acid beta-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.
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              Mitochondria are the powerhouses of immunity

              O’Neill and colleagues review the role of mitochondria dynamics and energetics in immunity and inflammation, in innate and adaptive immune cells.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                01 July 2022
                2022
                : 13
                : 919038
                Affiliations
                [1] 1 Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University , Nanjing, China
                [2] 2 Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University , Nanjing, China
                [3] 3 Department of Nephrology, Children’s Hospital of Nanjing Medical University , Nanjing, China
                Author notes

                Edited by: Uday Kishore, Brunel University London, United Kingdom

                Reviewed by: João Paulo Silva Nunes, University of São Paulo, Brazil; Takumi Koshiba, Fukuoka University, Japan; Fajian Hou, Chinese Academy of Sciences (CAS), China

                *Correspondence: Zhanjun Jia, jiazj72@ 123456hotmail.com ; Weiwei Xia, xiawwpku@ 123456163.com ; Yue Zhang, zyflora2006@ 123456hotmail.com

                †These authors have equally contributed to this work

                This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.919038
                9283757
                35844503
                32ee4e32-61d7-4bd2-bf63-1d2c739fb47c
                Copyright © 2022 Wang, Sun, Cao, Lin, Wu, Li, Yin, Zhou, Huang, Zhang, Zhang, Xia and Jia

                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.

                History
                : 13 April 2022
                : 06 June 2022
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 44, Pages: 16, Words: 7073
                Categories
                Immunology
                Original Research

                Immunology
                mavs,cardiac dysfunction,mitochondrial dysfunction,energy metabolism,oxidative stress
                Immunology
                mavs, cardiac dysfunction, mitochondrial dysfunction, energy metabolism, oxidative stress

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