Enzymatically modified, nonoxidized LDL induces selective adhesion and transmigration of monocytes and T-lymphocytes through human endothelial cell monolayers

Circulating monocytes and T lymphocytes extravasate through the endothelium at sites of developing atheromatous lesions, where they tend to accumulate and mediate the progression of the disease. We have previously demonstrate d the presence of an enzymatically degraded, nonoxidized form of LDL (E-LDL ) in early human fatty streaks, which possesses major biological properties of an atherogenic lipoprotein. The effects of E-LDL on human endothelial c ells have now been studied with respect to adhesion and transmigration of m onocytes and T lymphocytes. E-LDL induced a rapid and dose-dependent select ive adhesion of monocytes and T lymphocytes to endothelial cell monolayers within 30 minutes of incubation. Maximal increases in the number of adheren t monocytes (8-fold) and of adherent T lymphocytes (4-fold) were observed a fter treatment with 50 mu g/mL E-LDL, E-LDL was more active than oxidized L DL (ox-LDL), whereas native LDL produced only minor adhesive effects. Both E-LDL and ox-LDL enhanced transmigration of monocytes and of T lymphocytes through endothelial monolayers, Again, E-LDL was more potent than ox-LDL, i nducing transmigration to a similar extent as N-formyl-Met-Leu-Phe, In endo thelial cells, E-LDL stimulated upregulation of intercellular adhesion mole cule-1 (ICAM-1), platelet-endothelial cells adhesion molecule-1 (PECAM-1), P-selectin, and E-selectin with distinct kinetics. Analyses with blocking a ntibodies indicated that ICAM-1 and P-selectin together mediated approximat ely 70% of cell adhesion, whereas blocking of PECAM-1 had no effect on adhe sion but reduced transmigration to less than 50% of controls. E-LDL also up regulated expression of ICAM-1 in human aortic smooth muscle cells, and thi s correlated with increased adhesion of T lymphocytes. E-LDL is thus able t o promote the selective adhesion of monocytes and T lymphocytes to the endo thelium, stimulate transmigration of these cells, and foster their retentio n in the vessel wall by increasing their adherence to smooth muscle cells. These findings underline the potential significance of E-LDL in the pathoge nesis of atherosclerosis.