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.
Institute of Cardiovascular Science, Translational Medicine Institute, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
Am J Pathol. 2022 Jul;192(7):1016-1027. doi: 10.1016/j.ajpath.2022.03.013. Epub 2022 Apr 21.
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 (Med1) mice 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. 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.
中介体 1（MED1）是中介体复合物的关键亚基，与多种核受体相互作用，参与脂质代谢和能量稳态。已有研究报道，心肌细胞特异性 Med1 缺陷的小鼠会发生扩张型心肌病相关的心室扩张和心力衰竭。然而，巨噬细胞特异性 MED1 在心脏重构中的作用尚不清楚。在这项研究中，生成了巨噬细胞特异性 Med1 敲除（Med1）小鼠，并对其进行异丙肾上腺素（ISO）处理以诱导心脏纤维化，结果显示与 Med1 小鼠相比，这些小鼠的心脏纤维化程度加重。ISO 诱导心肌纤维化的 Med1 小鼠的心脏组织中，肌成纤维细胞转分化标志物基因[α-平滑肌肌动蛋白（SMA）]和促纤维化基因的表达水平显著升高，包括 Col1a1、Col3a1、Postn、Mmp2、Timp1 和 Fn1。特别是，转化生长因子（TGF）-β-Smad2/3 信号通路被激活。在骨髓来源的和腹腔巨噬细胞中，Med1 缺失也与促炎基因（包括 Il6、Tnfa 和 Il1b）的表达水平升高有关。这些发现表明，巨噬细胞特异性 MED1 缺失可能通过调节 TGF-β-SMAD2/3 通路加重 ISO 诱导的心脏纤维化，其潜在机制可能涉及 MED1 缺失触发巨噬细胞中炎症细胞因子的激活，进而可能刺激心脏成纤维细胞的表型转换并加速心脏纤维化。因此，MED1 是心脏纤维化的一个潜在治疗靶点。
