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Int. J. Mol. Sci. 2014, 15(4), 5536-5552; doi:10.3390/ijms15045536

BMP4 Enhances Foam Cell Formation by BMPR-2/Smad1/5/8 Signaling

1,†,* , 2,†
1 Department of Cerebral Vessels, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China 2 Department of Neurology, Shangluo Central Hospital, Shangluo 726000, Shaanxi, China 3 Department of Neurology, the Second Affiliated Hospital, Xi'an Medical College, Xi'an 710038, Shaanxi, China 4 Department of Neurology, Shaanxi Armed Police Corps Hospital, Xi'an 710054, Shaanxi, China 5 Department of Neurology, Xingyuan Hospital, Yulin 719000, Shaanxi, China 6 Department of Rehabilitation Medicine, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China 7 Department of Neurology, Xi'an Central Hospital, Xi'an 710003, Shaanxi, China These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 27 November 2013 / Revised: 9 January 2014 / Accepted: 12 February 2014 / Published: 31 March 2014
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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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.
Keywords: foam cell formation; BMP4; BMPR-2; Smad1/5/8 foam cell formation; BMP4; BMPR-2; Smad1/5/8
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Feng, J.; Gao, J.; Li, Y.; Yang, Y.; Dang, L.; Ye, Y.; Deng, J.; Li, A. BMP4 Enhances Foam Cell Formation by BMPR-2/Smad1/5/8 Signaling. Int. J. Mol. Sci. 2014, 15, 5536-5552.

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