Lipoprotein(a), Lp(a), is a low density lipoprotein (LDL) having as a protein moiety apoB100 linked by a single disulfide bridge to apolipoprotein(a), apo(a), a multikringle structure with a close homology to plasminogen. Lp(a) has been associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD). Vascular retention of Lp(a) via interactions with macromolecules of the extracellular matrix (ECM) of the arterial wall has been among the suggested mechanisms. Since in the atherosclerotic vessel Lp(a) is preferentially retained over LDL, a particle which only contains apoB100, this difference in retention is likely related to the presence of apo(a) in Lp(a). Our studies are designed to test the hypothesis. To this effect, we wish to define the molecular phenotype as well as derivatives thereof obtained by the action of elastases and metalloproteinases (MMPs) which cleave Lp(a)/apo(a). Complementary information will be obtained by using natural mutants of Lp(a) and products generated by recombinant techniques. In terms of proteoglycans (PG), we will continue our studies on decorin which we have already shown to bind to Lp(a) by both electrostatic (apoB100-glycosaminoglycan (GAG)) and hydrophobic interactions (apo(a)-decorin core protein) and extend these studies to the protein core of the other two main PG of the arterial intima, biglycan and versican. All of these PGs will be obtained by both recombinant technology and extraction from arterial tissues from cadavers. We will continue our studies on the binding of Lp(a) and derivatives to fibrinogen also with the goal of defining the molecular basis for the superbinding capacity for fibrinogen of Lp(a) species identified in the plasma of subjects at a high risk for atherosclerotic cardiovascular disease. Moreover the potential cardiovascular pathogenicity of the complexes formed from the in vitro interaction between Lp(a)/apo(a) and matrix macromolecules, will be examined for their susceptibility to the action of proteolytic enzymes with an emphasis on MMPs shown to independently cleave Lp(a)/apo(a) and matrix macromolecules. We will also determine the capacity of these complexes to interact with cultured human macrophages and their potential to stimulate these cells to synthesize and secrete MMPs capable of modifying Lp(a)/apo(a), PGs and derivatives thereof. Underlying these studies is the hypothesis, that the MMP-mediated changes in Lp(a)/apo(a) are favored by the inflammatory milieu of the human atheroma.
Showing the most recent 10 out of 13 publications
