Chen Xiaoqing, Zhang Wuchang, Wang Qian, Du Lili, Yi Yi, Liu Yan, Liu Xu, Duan Shengzhong
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao tong University, Shanghai, 200030, China.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, 200031, China.
Sci China Life Sci. 2016 Oct;59(10):1042-1047. doi: 10.1007/s11427-016-0037-y. Epub 2016 Jun 22.
The purpose of the present study was to study the impacts of eplerenone (EPL), an antagonist of mineralocorticoid receptors (MR), on atrial fibrosis in a mouse model with selective fibrosis in the atrium, and to explore the possible mechanisms. Using mutant TGF-β1 transgenic (Tx) mice, we first demonstrated that EPL inhibited atrial fibrosis specifically and decreased macrophage accumulation in the atria of these mice. Results from immunohistochemistry and western blotting showed that EPL attenuated protein expression of fibrosis-related molecules such as connective tissue growth factor (CTGF) and fibronectin in the atria of Tx mice. In culture, EPL inhibited gene expression of fibrosis-related molecules such as fibronectin, α-SMA, and CTGF in TGF-β1-stimulated atrial fibroblasts. Finally, using a co-culture system, we showed that TGF-β1-stimulated atrial fibroblasts induced migration of macrophages and this was blocked by EPL. EPL also blocked TGF-β1-induced gene expression of intedeukin-6 (IL-6) in atrial fibroblasts. Therefore, we conclude that EPL attenuated atrial fibrosis and macrophage infiltration in Tx mice. TGF-β1 and IL-6 were involved in the impacts of EPL on activation of atrial fibroblasts and interactions between fibroblasts and macrophages.
本研究的目的是在心房选择性纤维化的小鼠模型中，研究盐皮质激素受体（MR）拮抗剂依普利酮（EPL）对心房纤维化的影响，并探索其可能的机制。利用突变型转化生长因子-β1（TGF-β1）转基因（Tx）小鼠，我们首先证明EPL特异性抑制心房纤维化，并减少这些小鼠心房中的巨噬细胞积聚。免疫组织化学和蛋白质印迹结果显示，EPL减弱了Tx小鼠心房中纤维化相关分子如结缔组织生长因子（CTGF）和纤连蛋白的蛋白表达。在培养中，EPL抑制了TGF-β1刺激的心房成纤维细胞中纤维化相关分子如纤连蛋白、α-平滑肌肌动蛋白（α-SMA）和CTGF的基因表达。最后，利用共培养系统，我们表明TGF-β1刺激的心房成纤维细胞诱导巨噬细胞迁移，而这被EPL阻断。EPL还阻断了TGF-β1诱导的心房成纤维细胞中白细胞介素-6（IL-6）的基因表达。因此，我们得出结论，EPL减轻了Tx小鼠的心房纤维化和巨噬细胞浸润。TGF-β1和IL-6参与了EPL对心房成纤维细胞活化以及成纤维细胞与巨噬细胞之间相互作用的影响。
