APOLIPOPROTEIN(A) KRINGLE 4-CONTAINING FRAGMENTS IN HUMAN URINE - RELATIONSHIP TO PLASMA-LEVELS OF LIPOPROTEIN(A)

Apo(a) is a large glycoprotein of unknown function that circulates in plasma as parr of lipoprotein(a). Apo(a) is structurally related re pl asminogen and contains at least 10 kringle (K)4 repeats (type 1-10), a K5 repeat and sequences similar to the protease domain of plasminogen . Plasminogen generates two biologically active peptides: plasmin and angiostatin, a kringle-containing peptide. As a first step in determin ing if apo(a) generates a similar kringle-containing peptide, human ur ine was immunologically examined. Fragments ranging in size from 85 to 215 kD were immunodetected using antibodies directed against epitopes in the K4-type 2 repeat, but not the K4-type 9 repeat or protease dom ain. NH2-terminal sequence analysis revealed sequences specific for th e K4-type 1 repeat, confirming that the fragments are from the NH2 ter minus of the K4 array. The amount of urinary apo(a) rose in proportion to the plasma lipoprotein(a) concentration. Even individuals with tra ce to no apo(a) in plasma had immunodetectable apo(a) fragments in the ir urine. Intravenous administration of the human urinary apo(a) into mice resulted in the rapid appearance of the same sized fragments in t he urine. These findings suggest that the apo(a) fragments found in ur ine are formed extrarenally and then excreted by the kidney.