Abstract
Atherosclerosis and its complications are characterized by lipid-laden foam cell formation. Recently, an obvious up-regulation of BMP4 was observed in atherosclerotic plaque, however, its function and the underlying mechanism remains unknown. In our study, BMP4 pretreatment induced macrophage foam cell formation. Furthermore, a dramatic increase in the ratio of cholesteryl ester (CE) to total cholesterol (TC) was observed in BMP4-treated macrophages, accompanied by the reduction of cholesterol outflow. Importantly, BMP4 stimulation inhibited the expression levels of the two most important cellular cholesterol transporters ABCA1 and ABCG1, indicating that BMP4 may induce formation of foam cells by attenuating transporters expression. Further mechanism analysis showed that BMPR-2, one of the BMP4 receptors, was significantly increased in BMP4 treated macrophage foam cells. That blocking its expression using specific siRNA significantly increased ABCA1 and ABCG1 levels. Additionally, BMP4 treatment triggered the activation of Smad1/5/8 pathway by BMPR-2 signaling. After blocking the Smad1/5/8 with its inhibitor, ABCA1 and ABCG1 expression levels were up-regulated significantly, suggesting that BMP4 inhibited the expression of ABCA1 and ABCG1 through the BMPR-2/Smad1/2/8 signaling pathway. Therefore, our results will provide a new insight about how BMP4 accelerate the progressio of atherosclerosis, and it may become a potential target against atherosclerosis and its complications.
Highlights
Atherosclerosis is a chronic process resulting in clinically manifest coronary artery disease in middle age and later [1]
To evaluate the impact of BMP4 on foam cell formation, RAW 246.7 cells, mouse peritoneal macrophages (MPM) and PBMCs were co-incubated with oxidized LDL (ox-LDL), individually, with pretreatment of BMP4 or not
The present study has found that BMP4 accelerates macrophage foam cell formation, indicating its important role in atherosclerosis
Summary
Atherosclerosis is a chronic process resulting in clinically manifest coronary artery disease in middle age and later [1]. Lipid-laden foam cells are formed after phagocytosis of oxidized LDL (ox-LDL) by macrophage cells They confer one of the highest cardiovascular risks and initiate atherosclerotic progression. Aggressive lowering of lipid levels markedly reduces atherosclerotic coronary lesion, and increases the stability of vulnerable plaque. ABCA1 and ABCG1 are two known common regulators of intracellular cholesterol outflow that play an important role in regulating foam cell formation. Signaling increases lipid efflux, thereby reducing foam cell formation, intracellular lipid accumulation, and atherosclerosis [12,13]. BMP4 was found to be overexpressed in the atherosclerotic plaque, and was found to be crucial in cellular functions including vascular calcification, inflammation, and smooth muscle cell proliferation [17,18]. BMP receptor 2 (BMPR-2)/Smad1/5/8 signaling was evaluated
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