Macrophage metalloelastase, MMP-12, cleaves human apolipoprotein(a) in the linker region between kringles IV-4 and IV-5. Potential relevance to lipoprotein(a) biology.
In this study we found that macrophage metalloelastase, MMP-12 cleaves, in vitro, apolipoprotein(a) (apo(a)) in the Asn3518-Val3519 bond located in the linker region between kringles IV-4 and IV-5, a bond immediately upstream of the Ile3520-Leu3521 bond, shown previously to be the site of action by neutrophil elastase (NE). We have also shown that human apo(a) injected into the tail vein of control mice undergoes degradation as reflected by the appearance of immunoreactive fragments in the plasma and in the urine of these animals. To define whether either or both of these enzymes may be responsible for the in vivo apo(a) cleavage, we injected intravenously MMP-12(-/-), NE -/- mice and litter mates, all of the same strain, with either lipoprotein(a) (Lp(a)), full-length free apo(a), or its N-terminal fragment, F1, obtained by the in vitro cleavage of apo(a) by NE. In the plasma of Lp(a)/apo(a)-injected mice, F1 was detected in control and NE -/- mice but was virtually absent in the MMP-12(-/-) mice. Moreover, fragments of the F1 type were present in the urine of the animals except for the MMP-12(-/-) mice. These fragments were significantly smaller in size than those observed in the plasma. All of the animals injected with F1 exhibited small sized fragments in their urine. These observations provide evidence that, in the mouse strain used, MMP-12 plays an important role in the generation of F1 from injected human Lp(a)/apo(a) and that this fragment undergoes further cleavage during renal transit via a mechanism that is neither NE- nor MMP-12-dependent. Thus, factors influencing the expression of MMP-12 may have a modulating action on the biology of Lp(a).
Edelstein
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C
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. celina@medicine.bsd.uchicago.edu
Shapiro
S D
SD
Klezovitch
O
O
Scanu
A M
AM
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D053241:Apoprotein(a); D015153:Blotting, Western; D006801:Humans; D018082:Kringles; D019272:Leukocyte Elastase / Q000378:metabolism; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment
D001053:Apolipoproteins; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D053241:Apoprotein(a); D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12