Marein alleviates the development of atherosclerosis through targeting miR-126/lipoprotein-associated phospholipase A2 axis

Abstract

As a classical precious medicine, Coreopsis tinctoria Nutt. (C. tinctoria) is widely utilized for treatment of cardiometabolic diseases, while the important compound of C. tinctoria, marein exhibits multiple beneficial biological effects that related to the pathophysiological processes underlying atherogenesis. Thus, the purpose of present study is to investigate the role of marein on the development of atherosclerosis. In the current study, we observed that marein exhibited anti-inflammatory response function verified by reduced mRNA and protein levels of classical M1 but enhanced alternative M2 macrophage genes. Moreover, marein dramatically attenuated macrophage-induced foam cell formation with up-regulated cholesterol efflux but down-regulated cholesterol influx-related genes expression in bone marrow-derived macrophage (BMDMs) administrated with oxidized low-density lipoprotein (Ox-LDL), observed by staining with Oil-Red O, RT-PCR, or western blot analysis. Treatment of ApoE knockout mice (ApoE^−/−) with marein at indicated time which consistently fed with high-fat diet for 12 weeks was utilized to explore the function of marein on atherogenesis in vivo. We revealed that marein-treated group alleviated atherosclerotic plaques in the entire aorta and aortic root and inhibited plaque vulnerability characterized by decreased necrotic core, reduced macrophage, and lipid accumulation, whereas increased fibrous cap, enhanced smooth muscle cell, and collagen deposition. Importantly, we noticed that miR-126 could target to lipoprotein-associated phospholipase A₂ (Lp-PLA₂), and enhanced miR-126 but reduced Lp-PLA₂ expression was responsible for the alleviated function of marein on macrophage dysfunction. Collectively, we identified that marein could be a promising drug for prevention of the development of atherosclerosis by protecting against macrophage-mediated foam cell formation and inflammation, partially through miR-126/Lp-PLA₂ dependent mechanism.