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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Article Info
Publication History
Published online: April 21, 2022
Accepted:
March 31,
2022
Footnotes
Supported by National Natural Science Foundation of China grant 82070470 (L.B.); China Postdoctoral Science Foundation grants 2020M673424 and 2021T140541 (L.B.); and Innovation Capability Support Program of Shaanxi grants 2022PT-37 (L.B.), 2020PT-004 (S.Z.), and 2020PT-001 (E.L.).
Disclosures: None declared.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
