Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity.
Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.
Allen
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Department of Cardiothoracic Surgery, Imperial College of Science, Technology and Medicine, Royal Brompton and Harefield NHS Trust Hospital, Harefield Hospital, Harefield, Middlesex UB9 6JH, United Kingdom.
Khan
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Tam
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Sp
Koschinsky
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Taylor
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Yacoub
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D001161:Arteriosclerosis / Q000209:etiology*; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002704:Chlorates / Q000494:pharmacology; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology; D015536:Down-Regulation; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects*; D006023:Glycoproteins / Q000494:pharmacology; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein; D017270:Lipoprotein(a) / Q000494:pharmacology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis; D055293:Receptors, Urokinase Plasminogen Activator; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D000511:alpha-Macroglobulins / Q000494:pharmacology
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D002704:Chlorates; D019040:E-Selectin; D006023:Glycoproteins; D026563:LDL-Receptor Related Protein-Associated Protein; D017270:Lipoprotein(a); D026503:Low Density Lipoprotein Receptor-Related Protein-1; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; D019010:Vascular Cell Adhesion Molecule-1; D000511:alpha-Macroglobulins; D019765:Chondroitin ABC Lyase; D019763:Heparin Lyase; C032706:sodium chlorate