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Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating β1 integrin
Peggy T. Shih, … , Judith A. Berliner, Devendra K. Vora
Peggy T. Shih, … , Judith A. Berliner, Devendra K. Vora
Published March 1, 1999
Citation Information: J Clin Invest. 1999;103(5):613-625. https://doi.org/10.1172/JCI5710.
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Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating β1 integrin

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Abstract

We have shown previously that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) induces monocyte but not neutrophil binding. This monocyte binding was not mediated by endothelial E-selectin, P-selectin, vascular cell adhesion molecule-I, or intercellular adhesion molecule-I, suggesting an alternative monocyte-specific adhesion molecule. We now show that moncytic α4β1 integrins mediate binding to MM-LDL-treated endothelial cells. We present data suggesting that the expression of the connecting segment-1 (CS-1) domain of fibronectin (FN) is induced on the apical surface of HAEC by MM-LDL and is the endothelial α4β1 ligand in MM-LDL-treated cells. Although the levels of CS-1 mRNA and protein were not increased, we show that MM-LDL treatment causes deposition of FN on the apical surface by activation of β1integrins, particularly those associated with α5 integrins.Activation of β1 by antibody 8A2 also induced CS-1-mediated monocyte binding. Confocal microscopy demonstrated the activated β1 and CS-1colocalize in concentrated filamentous patches on the apical surface of HAEC. Both anti-CS-1 and an antibody to activated β1 showed increased staining on the luminal endothelium of human coronary lesions with active monocyte entry. These results suggest the importance of these integrin ligand interactions in human atherosclerosis.

Authors

Peggy T. Shih, Mariano J. Elices, Zhuang T. Fang, Tatiana P. Ugarova, Dana Strahl, Mary C. Territo, Joy S. Frank, Nicholas L. Kovach, Carlos Cabanas, Judith A. Berliner, Devendra K. Vora

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Figure 2

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Agents that block monocyte/endothelial interactions in vitro. HAEC were ...
Agents that block monocyte/endothelial interactions in vitro. HAEC were stimulated with 250 μg/ml MM-LDL at 37°C for 4 h. Human monocytes were incubated with 5 μg/ml anti-α4, β1, β2, or β7 for 30 min before addition to the endothelial cell layer. Unbound monocytes were rinsed off and the cells fixed with 1% gluteraldehyde in 1× PBS. Anti-α4 and anti-β1 both significantly reduced the number of monocytes bound to the endothelial cell layer. Neither anti-β2 nor anti-β7 demonstrated an effect on the level of monocytes bound (a). In a separate study, HAEC were treated as just described and monocytes were incubated with either active CS-1 (500 μg) or scrambled peptide (500 μg) for 20 min at room temperature. A binding assay was performed as just described. The active CS-1 peptide significantly reduced the levels of bound monocytes, whereas the scrambled peptide did not affect the levels bound (b). In the last experiment, HAEC were treated with MM-LDL, as described, before being incubated with blocking antibodies to VCAM-1 (4B9), polyclonal FN, 90.45, or 7E5 at 5 μg/ml for 30 min. Untreated monocytes were used to perform the binding assay. The antibody against VCAM-1 did not reduce the number of monocytes bound to MM-LDL–stimulated HAEC. However, FN, 90.45, and 7E5 antibodies all significantly reduced monocyte adhesion (c). For each condition, the number of monocytes was determined by visually counting four fields per well in four separate wells. Additionally, all experiments are representative of four separate studies. Values represent mean ± SD (n = 12). *P < 0.0005. CS-1, connecting segment-1; HAEC, human aortic endothelial cells; MM-LDL, minimally modified low-density lipoprotein; VCAM-1, vascular cell adhesion molecule-1; APBS, PBS + BSA; GNS, goat normal serum.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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