Abstract 211: MKL1 Affects Proliferation/Survival Property of Pro-Atherogenic Macrophages

Abstract

Coronary artery disease (CAD) is one of the leading causes of death in the most countries. Atherosclerosis of coronary arteries often results in high incidence of vascular occlusion and is recognized as the major cause of CAD. We have previously reported from a genome-wide association study that a promoter SNP in megakaryoblastic leukemia 1 gene ( MKL1 ), which conferred higher transcriptional activity, was significantly associated with the susceptibility to CAD as well as coronary atherosclerosis. MKL1 is a Rho-Rock signaling-responsive co-activator of serum response factor, and regulates a variety of cellular functions. We found that MKL1 was highly expressed in activated macrophages in the neointima of atherosclerotic lesions from human and ApoE-knockout (KO) mouse. In addition, the expression level of MKL1 in lesional macrophages was increased during the development of atherosclerosis in ApoE-KO mice. We have established a transgenic mouse line, MKL1-TgM, in which human MKL1 was specifically overexpressed in monocyte/macrophage lineage cells. In this study, MKL1-TgM was crossbred onto ApoE-KO background. ApoE-KO/MKL1-TgM fed with normal chow developed severer atherosclerosis and showed poorer survival rate than ApoE-KO mice. Serum level of pro-inflammatory cytokines was increased in ApoE-KO/MKL1-TgM. Interestingly, ApoE-KO/MKL1-TgM also developed hypertriglyceridemia, which was associated with severe lipodystrophy. We also investigated how MKL1 regulated macrophages function. Recently, local proliferation/accumulation of lesional macrophages was reported to be a crucial event in atherosclerosis. We treated bone marrow-derived macrophages (BMDMs) with stimuli, such as M-CSF or OxLDL, and found that proliferation property of BMDMs from MKL1-TgM was elevated. On the other hand, BMDMs from MKL1-TgM were more resistant to apoptosis. Furthermore, immunohistochemistry analyses of lesional macrophages in ApoE-KO/MKL1-TgM showed enhanced proliferation and mitigated apoptosis. Taken together, our data indicated that MKL1 would contribute to the development of atherosclerosis by modulating pro-atherogenic functions of macrophages, providing a potential molecular target for the therapy and prevention of atherosclerosis.