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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063115-04
Application #
6537634
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Applebaum-Bowden, Deborah
Project Start
1999-07-16
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$299,321
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Edelstein, Celina; Yousef, Mohammed; Scanu, Angelo M (2005) Elements in the C terminus of apolipoprotein [a] responsible for the binding to the tenth type III module of human fibronectin. J Lipid Res 46:2673-80
Scanu, Angelo M; Hinman, Janet; Pfaffinger, Ditta et al. (2004) Successful utilization of lyophilized lipoprotein(a) as a biological reagent. Lipids 39:589-93
Scanu, Angelo M (2003) Lipoprotein(a) and the atherothrombotic process: mechanistic insights and clinical implications. Curr Atheroscler Rep 5:106-13
Edelstein, Celina; Pfaffinger, Ditta; Hinman, Janet et al. (2003) Lysine-phosphatidylcholine adducts in kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein(a). J Biol Chem 278:52841-7
Scanu, Angelo M; Hinman, Janet (2002) Issues concerning the monitoring of statin therapy in hypercholesterolemic subjects with high plasma lipoprotein(a) levels. Lipids 37:439-44
Klezovitch, O; Edelstein, C; Scanu, A M (2001) Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein(a). Evidence for a critical involvement of elements in its C-terminal domain. J Biol Chem 276:46864-9
Nakajima, K; Hinman, J; Pfaffinger, D et al. (2001) Changes in plasma triglyceride levels shift lipoprotein(a) density in parallel with that of LDL independently of apolipoprotein(a) size. Arterioscler Thromb Vasc Biol 21:1238-43
Klezovitch, O; Scanu, A M (2001) Domains of apolipoprotein E involved in the binding to the protein core of biglycan of the vascular extracellular matrix: potential relationship between retention and anti-atherogenic properties of this apolipoprotein. Trends Cardiovasc Med 11:263-8
Edelstein, C; Nakajima, K; Pfaffinger, D et al. (2001) Oxidative events cause degradation of apoB-100 but not of apo[a] and facilitate enzymatic cleavage of both proteins. J Lipid Res 42:1664-70
Scanu, A M; Nakajima, K; Edelstein, C (2001) Apolipoprotein(a): structure and biology. Front Biosci 6:D546-54

Showing the most recent 10 out of 13 publications