THE BINDING-ACTIVITY OF THE MACROPHAGE LIPOPROTEIN(A) APOLIPOPROTEIN(A) RECEPTOR IS INDUCED BY CHOLESTEROL VIA A POSTTRANSLATIONAL MECHANISM AND RECOGNIZES DISTINCT KRINGLE DOMAINS ON APOLIPOPROTEIN(A)

Elevated plasma levels of lipoprotein(a) (Lp(a)) can be a risk factor for atherosclerosis, and the interaction of Lp(a) with cholesterol-loa ded macrophages (foam cells) in atheromata may be important in Lp(a)-i nduced atherogenesis, We have previously shown that when cultured macr ophages are loaded with cholesterol, they acquire the ability to inter nalize and lysosomally degrade Lp(a) via interaction bet2een a novel c ell-surface receptor activity and the apolipoprotein(a) (apo(a)) moiet y of Lp(a). Herein we explore the cell-surface binding of recombinant apo(a) (r-apo(a)) by foam cells, Whereas the induction of degradation of r-apo(a) by cholesterol loading of macrophages depended on new prot ein synthesis, the induction of binding of r-apo(a) did not, Furthermo re, J774 macrophages bound r-apo(a) in a cholesterol-regulatable and s pecific manner but degraded r-apo(a) poorly. Thus, the binding and int ernalization/degradation functions of the receptor activity are distin ct, To explore which domains on r-apo(a) interact with the foam cell r eceptor, we conducted a series of competitive and direct binding and d egradation experiments using 12 r-apo(a) constructs that differed in t heir content of specific kringle subtypes. These data, as well as comp lementary data with anti-apo(a) monoclonal antibodies, indicated that the region centered around kringle type IV, subtypes 6-7 (KIV6-7) is i mportant in receptor binding, Remarkably, a cholesterol-induced recept or activity with similar structural specificity was also found on Chin ese hamster ovary cells, In conclusion, the foam cell Lp(a)/apo(a) rec eptor consists of a cholesterol-regulatable binding activity and a sho rt-lived component necessary for internalization or lysosomal degradat ion; the binding activity interacts with a distinct region of apo(a) t hat is different from that involved in competition for plasminogen bin ding.