MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages

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.