Role of various tissues in apo(a) fragmentation and excretion of fragmentsby the kidney

Background Lipoprotein(a) [Lp(a)] is an atherothrombotic plasma lipoprotein with unknown function. Little is known about the catabolism of this lipopr otein, in particular the steps related to apolipoprotein(a) [apo(a)] fragme ntation and excretion by the kidney. Material and methods High plasma levels (up to 9 mg dL(-1)) of the N-termin al fragment of apo(a) were expressed in mice by adenovirus mediated gene tr ansfer. Plasma of such N-apo(a) mice was injected into acceptor mice and th e fragmentation and urinary secretion of N-apo(a) were followed by immunoch emical techniques. Results Mice transduced with N-Ad expressed apo(a)-fragments with 3-11 krin gle-IV (KIV) repeats. Injection of N-apo(a)-plasma from donor mice into acc eptor mice resulted in fragmentation of N-apo(a)s with 3-11 KIVs yielding s maller peptides down to 2 KIVs. Secretion of N-apo(a)-fragments with 2 to m aximally 6 KIVs into urine occurred as early as 2 min after injection. Immu nohistochemical studies of kidney suggested filtration as a mechanism of ap o(a)-fragment excretion. When N-apo(a) was incubated in vitro with various tissues from perfused mic e, skeletal muscle and kidney followed by liver and spleen contributed to f ragmentation. Tissues from unperfused organs, or the addition of normal mou se 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 metalloprotei nases located on skeletal muscle, kidney and other organs. Small apo(a)frag ments up to a size of 6 KIVs are excreted into urine, yet a major portion o f apo(a) fragments is removed from circulation extrarenally.