MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages
MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages
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DOI：
10.1016/j.yjmcc.2019.05.015
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Kimura, Akinori
中科院分区：
文献类型：
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作者：
An, Jianbo;Naruse, Taeko K.;Kimura, Akinori
我们之前报道过心肌素相关转录因子A （MRTF-A）启动子多态性与冠状动脉粥样硬化相关。然而，MRTF-A在动脉粥样硬化发展中的作用尚不清楚。巨噬细胞是动脉粥样硬化的重要介质。研究表明，巨噬细胞的局部增殖和存活具有致动脉粥样硬化的作用。在本研究中，我们发现MRTF-A在人颈动脉粥样硬化斑块的病变巨噬细胞中高表达。我们随后研究了巨噬细胞MRTF-A在动脉粥样硬化发病机制中的作用。建立ApoE无MRTF-A转基因小鼠(ApoE(-/-)/MRTF-A(tg/+))，其中人类MRTF-A在单核细胞/巨噬细胞中特异性过表达，并饲喂正常饮食，观察动脉粥样硬化的进展情况。我们发现ApoE(-/-)/MRTF-A（tg/+）加重动脉粥样硬化和病变巨噬细胞在ApoE(-/-)/MRTF-A（tg/+）的主动脉窦中比ApoE（-/-）的幼崽更明显地积聚。我们还发现MRTF-A在体外和体内均能促进巨噬细胞的增殖和减轻细胞凋亡，并下调细胞周期蛋白依赖性激酶抑制剂的表达。根据这些发现，我们得出结论，MRTF-A调节促动脉粥样硬化巨噬细胞的功能特性。我们的研究可能对了解巨噬细胞MRTF-A在动脉粥样硬化进展中的病理作用具有重要意义。
We have previously reported that promoter polymorphism of myocardin-related transcription factor A (MRTF-A) is associated with coronary atherosclerosis. However, the contribution of MRTF-A to the development of atherosclerosis remains unknown. Macrophages are known to be important mediators of atherosclerosis. It has been demonstrated that local proliferation and survival of macrophages are atherogenic. In this study, we found that MRTF-A was highly expressed in lesional macrophages in human carotid atherosclerotic plaque. We then investigated the role of macrophagic MRTF-A in the pathogenesis of atherosclerosis. ApoE null MRTF-A transgenic mice (ApoE(-/-)/MRTF-A(tg/+)), in which human MRTF-A was specifically overexpressed in monocytes/ macrophages, were established and fed with normal diet to examine the progression of atherosclerosis. We found that ApoE(-/-)/MRTF-A(tg/+) aggravated atherosclerosis and lesional macrophages were more prominently accumulated in the aortic sinus of ApoE(-/-)/MRTF-A(tg/+) than in that of ApoE(-/-) littermates. We also found that MRTF-A promoted proliferation and mitigated apoptosis of macrophages both in vitro and in vivo, and down regulated the expression of cyclin-dependent kinase inhibitors. From these findings, we conclude that MRTF-A modulates functional properties of pro-atherogenic macrophages. Our study may play a valuable role in understanding the pathological role of macrophagic MRTF-A in the progression of atherosclerosis.