Date of Award

2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Koschinsky, Marlys

Keywords

atherosclerosis; inflammation; Lipoprotein(a); macrophage; oxidized phospholipid; thrombosis

Rights

CC BY-NC-ND 4.0

Abstract

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) have been identified as a causal risk factor for calcific aortic valve disease (CAVD) and coronary heart disease (CHD). Relationships have recently been identified for genetic factors, such as single nucleotide polymorphisms (SNPs) in the LPA gene, specifically r10455872 and rs3798220, that have been correlated with increased Lp(a) plasma levels and risk of cardiovascular disease (CVD). Apo(a) bears striking homology with the zymogen plasminogen and possesses several similar structural features. A key feature shared between these proteins is the presence of multiple repeats of a kringle domain, which possesses the ability to bind to exposed lysine residues with high affinity. Apo(a) contains several copies of a plasminogen like KIV domain, one of which, KIV10, has been implicated in many proinflammatory processes in vitro. It has been hypothesized that the proinflammatory potential of Lp(a)/apo(a) is derived from the ability to be covalently modified by an oxidized phosphatidylcholine (oxPC) moiety. The work in this dissertation assesses the mechanism by which the oxPC moiety on apo(a) stimulates interleukin-8 (IL-8) production in macrophages. Targeted mutagenesis was used to determine a role for the KIV10 strong lysine binding site (sLBS) in the covalent addition of the oxPC moiety on apo(a) and identified the site of covalent oxPC modification at the amino acid level. Furthermore, characterization of the I4399M variant of apo(a), resulting from the rs3798220 SNP, from a perspective of its distinct structural and functional properties, revealed roles for the polymorphism on the structure and permeability of purified fibrin and plasma clots. The enhanced prothrombotic potential of this variant may be a result of an oxidized methionine residue, as identified by mass spectrometry. The identification of distinct functional properties associated with the oxidative modification of Lp(a)/ apo(a) offers insights into its proatherosclerotic and prothrombotic potentials.

Available for download on Thursday, October 26, 2017

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