PROTEOLYTIC DEGRADATION OF LOW-DENSITY-LIPOPROTEIN BY LIPOPROTEIN(A) AND BY RECOMBINANT APO(A)

The plasma concentration of lipoprotein(a) (Lp(a)) is correlated with the risk of atherosclerosis, and both Lp(af and LDL are present in ath erosclerotic lesions. Lp(a) is similar in structure to LDL, its distin guishing feature from LDL being the presence of one additional glycopr otein, apo(a), that is linked to apoB-100. Upon incubation of I-125-LD L with isolated Lp(a), we found a dose and time-dependent increase in the proportion of TCA-soluble radioactive material, demonstrating degr adation of LDL. The addition of unlabelled LDL. decreased the degradat ion of I-125-LDL, while MDL or albumin had no such effect. Recombinant DNA-derived apo(a), R-apo(a), which itself expressed no amidolytic ac tivity, displayed an increase in amidolytic activity after pre-incubat ion with LDL. Furthermore, activated R-apo(a) caused degradation of I- 125-LDL. Treatment of R-apo(a) with phenylmethanesulfonyl fluoride inh ibited LDL apoB-100 degradation, indicating that R-apo(a) has serine e sterase type proteolytic activity. The results show that apo(a) is act ivated in the presence of LDL, and that this activation leads to prote olytic modification of LDL. The induction of apo(a) proteolytic activi ty by LDL suggests a novel mechanism whereby Lp(a) may be atherogenic.