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  • Title: Polymorphonuclear cells isolated from human peripheral blood cleave lipoprotein(a) and apolipoprotein(a) at multiple interkringle sites via the enzyme elastase. Generation of mini-Lp(a) particles and apo(a) fragments.
    Author: Edelstein C, Italia JA, Scanu AM.
    Journal: J Biol Chem; 1997 Apr 25; 272(17):11079-87. PubMed ID: 9111002.
    Abstract:
    Incubation of polymorphonuclear cells (PMN), isolated from human peripheral blood, with either lipoprotein(a) (Lp(a)) or free apolipoprotein(a) (apo(a)), derived from the parent Lp(a), caused in both cases a multisite fragmentation of apo(a) inhibited by methoxysuccinyl-Ala-Ala-Pro-Val-CH2Cl, a specific elastase inhibitor. The major cut site was at the interkringle region between apo(a) kringles IV-4 and IV-5 (Ile3520-Leu3521). The other cleavages were between kringles IV-7 and IV-8 (Thr3846-Leu3847) and between kringles IV-10 and V (Ile4196-Gln4197). The elastase-induced fragmentation of apo(a) was the same whether free or as a member of Lp(a), indicating that the disulfide bond between apo(a) and the apoB100 component of Lp(a) did not hinder the elastase action. Lp(a) fragments containing kringle IV-9 retained the linkage to apoB100 via the disulfide bond, forming mini-Lp(a) particles in which the size of apo(a) varied according to the size of the fragments produced by the elastase digestion. The proteolytic fragmentation was unaffected by apo(a) size polymorphism within the range examined. PMN elastase also caused a partial proteolysis of apoB100 whether as a component of Lp(a), Lp(a) freed of apo(a), or authentic low density lipoprotein without an apparent destabilization of these lipoprotein particles. Proteolysis of Lp(a) by PMN was due to an elastase activity that was 3.5% of that observed when PMN were activated by N-formyl-Met-Leu-Phe. A portion of the released elastase was found to be associated in an active form with both Lp(a) and low density lipoprotein even in an ultracentrifugal field at high salt concentrations. Taken together, our results indicate that apo(a) undergoes important proteolytic modifications by PMN elastase, which exhibits specificity for peptide bonds located in the interkringle domains of apo(a). In the case of Lp(a), elastase cleavage causes the formation of mini-Lp(a) particles with a protein moiety containing a truncated apo(a). Elastase-mediated proteolytic events may occur in vivo under conditions associated with either an excessive leakage of elastase from PMN and/or deficiencies of natural inhibitors of this enzyme.
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