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MED1 Deficiency in Macrophages Aggravates Isoproterenol-Induced Cardiac Fibrosis in Mice

  • Mehreen Fatima
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Jie Gao
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Tuo Han
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China
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  • Yiming Ding
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China
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  • Yali Zhang
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Ergang Wen
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Linying Jia
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Rong Wang
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Weirong Wang
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Sihai Zhao
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Liang Bai
    Correspondence
    Address correspondence to Liang Bai, Ph.D., or Enqi Liu, Ph.D., Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
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  • Enqi Liu
    Correspondence
    Address correspondence to Liang Bai, Ph.D., or Enqi Liu, Ph.D., Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
    Affiliations
    Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China

    Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China
    Search for articles by this author
      Mediator 1 (MED1), a key subunit of the mediator complex, interacts with various nuclear receptors and functions in lipid metabolism and energy homeostasis. Dilated cardiomyopathy–related ventricular dilatation and heart failure have been reported in mice with cardiomyocyte-specific Med1 deficiency. However, the contribution of macrophage-specific MED1 in cardiac remodeling remains unclear. In this study, macrophage-specific Med1 knockout (Med1ΔMac) mice were generated and exposed to isoproterenol (ISO) to induce cardiac fibrosis; these mice showed aggravated cardiac fibrosis compared with Med1fl/fl mice. The levels of expression of marker genes for myofibroblast transdifferentiation [α-smooth muscle actin (SMA)] and of profibrotic genes, including Col1a1, Col3a1, Postn, Mmp2, Timp1, and Fn1, were significantly increased in the cardiac tissues of Med1ΔMac mice with ISO-induced myocardial fibrosis. In particular, the transforming growth factor (TGF)-β–Smad2/3 signaling pathway was activated. In bone marrow–derived and peritoneal macrophages, Med1 deficiency was also associated with elevated levels of expression of proinflammatory genes, including Il6, Tnfa, and Il1b. These findings indicate that macrophage-specific MED1 deficiency may aggravate ISO-induced cardiac fibrosis via the regulation of the TGF-β–SMAD2/3 pathway, and the underlying mechanism may involve MED1 deficiency triggering the activation of inflammatory cytokines in macrophages, which in turn may stimulate phenotypic switch of cardiac fibroblasts and accelerate cardiac fibrosis. Thus, MED1 is a potential therapeutic target for cardiac fibrosis.
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