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

Mediator of RNA polymerase II transcription subunit (MED)-1, a key subunit of the mediator complex, interacts with various nuclear receptors to regulate transcriptional machinery. MED1 has roles 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, mice with macrophage-specific Med1 knockout (Med1 ) were generated and exposed to isoproterenol (ISO) to induce cardiac fibrosis; these mice showed aggravated cardiac fibrosis compared with Med1 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 Med1 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. Based on these findings, in humans, 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 be 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 may be considered as a potential therapeutic target for cardiac fibrosis.