LIPOPROTEIN(A) IS A POTENT CHEMOATTRACTANT FOR HUMAN PERIPHERAL MONOCYTES

We have previously reported that the serine protease plasmin triggers chemotaxis in human peripheral monocytes, but not in polymorphonuclear leukocyte. We now show that the structurally related lipoprotein(a) ( Lp[al) as well as recombinant apolipoprotein(a) (apo[a]) trigger chemo tactic responses in human monocytes equipotent to that observed with t he standard chemoattractant FMLP. The chemotactic effects of Lp(a) and FMLP were additive. Low density lipoprotein (LDL) did not elicit any significant chemotactic response nor did it interfere with that trigge red by Lp(a). As assessed by checkerboard analysis, Lp(a)-mediated mon ocyte locomotion was a true chemotaxis. Both plasminogen as well as ca talytically inactivated plasmin inhibited monocyte migration elicited by Lp(a), suggesting binding of Lp(a) to plasminogen binding sites. Lp (a)-mediated signaling proceeds through a pertussis toxin-sensitive gu anosine triphosphate (GTP)-binding protein and activation of protein k inase C as implicated by the effects of 1-O-hexadecyl-2-O-methyl-rac-g lycerol and chelerythrine. Lp(a) induced generation of guanosine 3',5' -cyclic monophosphate (cGMP), apparently crucial for the Lp(a)-mediate d chemotaxis, because an inhibitor of soluble guanylyl cyclase, LY8358 3, reduced both the Lp(a)-induced cGMP formation as well as the monocy te migration. The latter effect of LY83583 was antagonized by the stab le cGMP analog 8-pCPT-cGMP. The data indicate that kp(a) triggers chem otaxis in human monocytes by way of a cGMP-dependent mechanism. Our fi ndings may have important implications for the atherogenesis associate d with elevated levels of Lp(a). (C) 1997 by The American Society of H ematology.