Expression of adhesion molecules by Lp(a): a potential novel mechanism forits atherogenicity

Lp(a) is a major inherited risk factor for premature atherosclerosis. The m echanism of Lp(a) atherogenicity has not been elucidated, but likely involv es both its ability to interfere with plasminogen activation and its athero genic potential as a lipoprotein particle after receptor-mediated uptake. W e demonstrate that Lp(a) stimulates production of vascular cell. adhesion m olecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothe lial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calciu m 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 mole cules was not prevented by an antibody (IgGC7) to the LDL receptor or by re ceptor-activating protein, an antagonist of ligand binding to the VLDL rece ptor. Addition of alpha(2)-macroglobulin as well as treatment with heparina se, chondroitinase,ABC, and sodium chlorate did not decrease levels of VCAM -1 and E-selectin stimulated by Lp(a), suggesting that neither the low dens ity lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the b inding 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 l ysine analog E-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexaneca rboxymethylic acid (tranexamic acid), which acts by binding to the lysine b inding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuat ed 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 pot ent surface expression of VCAM-1 and E-selectin that does not appear to inv olve any of the known potential Lp(a) binding sites. Because leukocyte recr uitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating e ffect of Lp(a) places it at a crucial juncture in the initiation of atherog enic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.