Assessing the structure-function relationships of the apolipoprotein(a) kringle IV sub-type 10 domain

Matthew J. Borrelli, The University of Western Ontario

Abstract

Elevated plasma lipoprotein(a) (Lp(a)) is the most prevalent heritable risk factor in the development of cardiovascular disease. The apolipoprotein(a) (apo(a)) component of Lp(a) is strongly implicated in the pathogenicity of Lp(a). It is hypothesized that the inflammatory potential of Lp(a)/apo(a) is mediated by the lysine binding ability of the apo(a) kringle IV10 (KIV10) domain, along with its covalently bound oxidized phospholipid (oxPL). Using targeted mutagenesis, two novel null alleles for the LPA gene that generate non-secretable apo(a) species have been identified, resulting from amino acid substitutions in the KIV10 domain. A potential mechanism by which KIV10 oxPL modification is enriched was identified. Finally, RNA-Seq was utilized to demonstrate gene regulation in macrophage-like cells in response to the lysine binding function and covalent oxPL of the KIV10 domain. It was determined that the lysine binding ability and covalent oxPL of apo(a) KIV10 are both implicated in vascular cell inflammation and atherosclerosis.