title: BMP4 enhances foam cell formation by BMPR-2/Smad1/5/8 signaling.
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.
authors.affiliation: Department of Cerebral Vessels, First Afﬁliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. junfengxian@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Neurology, Shangluo Central Hospital, Shangluo 726000, Shaanxi, China. jiangfei_gao@163.com.
authors.forename: Jiangfei
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Neurology, the Second Afﬁliated Hospital, Xi'an Medical College, Xi'an 710038, Shaanxi, China. yuxin_lisx@163.com.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Shaanxi Armed Police Corps Hospital, Xi'an 710054, Shaanxi, China. yanhua_yangxa@163.com.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xingyuan Hospital, Yulin 719000, Shaanxi, China. lili_dang@163.com.
authors.forename: Lili
authors.initials: L
authors.lastname: Dang
authors.affiliation: Department of Cerebral Vessels, First Afﬁliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. yuanpeng_ye@163.com.
authors.forename: Yuanpeng
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Rehabilitation Medicine, First Afﬁliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. jingyuan_deng@163.com.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Neurology, Xi'an Central Hospital, Xi'an 710003, Shaanxi, China. antai_li@126.com.
authors.forename: Antai
authors.initials: A
authors.lastname: Li
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D001692:Biological Transport; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis; D008074:Lipoproteins / Q000096:biosynthesis*; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D051898:Smad1 Protein / Q000235:genetics; D051902:Smad5 Protein / Q000235:genetics; D051904:Smad8 Protein / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II; D002788:Cholesterol Esters; D008055:Lipids; D008074:Lipoproteins; D034741:RNA, Small Interfering; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C525810:Bmp4 protein, mouse; C497401:Smad1 protein, mouse; C497798:Smad5 protein, mouse; C491621:Smad9 protein, mouse; C498219:Bmpr2 protein, mouse