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Role of various tissues in apo(a) fragmentation and excretion of fragments by the kidney
Author(s) -
Frank S.,
Hrzenjak A.,
Blaschitz A.,
Dohr G.,
Kostner G. M.
Publication year - 2001
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1046/j.1365-2362.2001.00811.x
Subject(s) - medicine , endocrinology , kidney , apolipoprotein b , fragmentation (computing) , excretion , leupeptin , chemistry , biology , microbiology and biotechnology , biochemistry , protease , enzyme , cholesterol , ecology
Background Lipoprotein(a) [Lp(a)] is an atherothrombotic plasma lipoprotein with unknown function. Little is known about the catabolism of this lipoprotein, in particular the steps related to apolipoprotein(a) [apo(a)] fragmentation and excretion by the kidney. Material and methods High plasma levels (up to 9 mg dL −1 ) of the N‐terminal fragment of apo(a) were expressed in mice by adenovirus mediated gene transfer. Plasma of such N‐apo(a) mice was injected into acceptor mice and the fragmentation and urinary secretion of N‐apo(a) were followed by immunochemical techniques. Results Mice transduced with N‐Ad expressed apo(a)‐fragments with 3–11 kringle‐IV (KIV) repeats. Injection of N‐apo(a)‐plasma from donor mice into acceptor mice resulted in fragmentation of N‐apo(a)s with 3–11 KIVs yielding smaller peptides down to 2 KIVs. Secretion of N‐apo(a)‐fragments with 2 to maximally 6 KIVs into urine occurred as early as 2 min after injection. Immunohistochemical studies of kidney suggested filtration as a mechanism of apo(a)‐fragment excretion. When N‐apo(a) was incubated in vitro with various tissues from perfused mice, skeletal muscle and kidney followed by liver and spleen contributed to fragmentation. Tissues from unperfused organs, or the addition of normal mouse plasma, caused marked reduction in N‐apo(a) fragmentation. EDTA, and not aprotinin or leupeptin, prevented apo(a) cleavage. Conclusion Here we provide evidence that apo(a) is cleaved by metalloproteinases located on skeletal muscle, kidney and other organs. Small apo(a)‐fragments up to a size of 6 KIVs are excreted into urine, yet a major portion of apo(a) fragments is removed from circulation extrarenally.