scholarly journals Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

2011 ◽  
Vol 286 (14) ◽  
pp. 12213-12220 ◽  
Author(s):  
Xin Su ◽  
Lihua Ao ◽  
Yi Shi ◽  
Thomas R. Johnson ◽  
David A. Fullerton ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Bone Morphogenetic Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Bone Morphogenetic Protein 2 ◽  
Low Density ◽  
Toll Like Receptors ◽  
Oxidized Low Density Lipoprotein ◽  
Morphogenetic Protein

Abstract 3932: Central Role Of Toll-like Receptor 4 In Oxidized Low Density Lipoprotein-and Lipopolysaccharide-Induced Bone Morphogenetic Protein-2 Expression In Human Coronary Artery Endothelial Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xin Su ◽  
Thomas R Johnson ◽  
Lihua Ao ◽  
Bruce L Paschall ◽  
Xiaoping Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Bone Morphogenetic Protein 2 ◽  
Toll Like Receptor ◽  
Oxidized Low Density Lipoprotein ◽  
Human Coronary Artery ◽  
Toll Like Receptor 4 ◽  
Morphogenetic Protein

Previous studies demonstrated that osteogenic mediators, in particular bone morphogenetic protein-2 (BMP-2), play an important role in the progression of atherosclerosis and vascular calcification. Although it is known that the atherogenic factor oxidized low density lipoprotein (oxLDL) up-regulates BMP-2 expression in endothelial cells, the signaling mechanisms involved are not well understood. In macrophages, oxLDL up-regulates Toll-like receptor 4 (TLR4) expression, and this innate immunoreceptor appears to be involved in oxLDL-induced macrophage actin polymerization. We earlier found that stimulation of TLR4 with lipopolysac-charide (LPS) increases cellular BMP-2 protein levels in human aortic valve interstitial cells. We hypothesized that the TLR4 pathway plays a central role in mediating BMP-2 expression in human coronary artery endothelial cells (CAECs). The purposes of this study were to examine whether TLR4 mediates oxLDL- and/or LPS-induced BMP-2 expression in human CAECs, and to determine whether the p38 and/or p44/42 MAPKs are involved. Methods and results : Stimulating human CAECs with LPS (E. coli 0111:B4, 200 ng/ml) for 24 h up-regulated BMP-2 protein expression. Similarly, stimulation with oxLDL (from human plasma, CuSO 4 -oxidized, LPS-free, 40–160 μg/ml) for 24 h induced BMP-2 expression in a dose-dependent manner. Pretreatment with either TLR4-neutralizing antibody or TLR4 siRNA significantly attenuated oxLDL-induced BMP-2 expression and abrogated the effect of LPS on BMP-2 expression. Over-expression of TLR4 enhanced the cellular BMP-2 response to oxLDL and LPS. Further, immunofluorescent staining co-localized oxLDL with TLR4. Although LPS induced ICAM-1 expression in human CAECs, oxLDL had no effect, indicating that oxLDL and LPS have different pro-inflammatory effects. BMP-2 expression was associated with activation of p38 and p44/42 MAPKs. Inhibiting p44/42, but not p38, reduced BMP-2 expression. Conclusions: In human CAECs, TLR4 plays a central role in regulating BMP-2 expression induced by either oxLDL or LPS, and the signaling mechanism involves the p44/42 MAPK pathway. These novel findings underscore an important role of TLR4 in atherosclerosis and vascular calcification.

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