Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)1

Gregor Leibundgut; Corey Scipione; Huiyong Yin; Matthias Schneider; Michael B. Boffa; Simone Green; Xiaohong Yang; Edward Dennis; Joseph L. Witztum; Marlys L. Koschinsky; Sotirios Tsimikas

Journal of Lipid Research (Oct 2013)

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)1

Gregor Leibundgut,
Corey Scipione,
Huiyong Yin,
Matthias Schneider,
Michael B. Boffa,
Simone Green,
Xiaohong Yang,
Edward Dennis,
Joseph L. Witztum,
Marlys L. Koschinsky,
Sotirios Tsimikas

Affiliations

Gregor Leibundgut: Departments of Medicine, University of California, San Diego, La Jolla, CA; University of Basel, Basel, Switzerland
Corey Scipione: Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada
Huiyong Yin: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and
Matthias Schneider: Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, University of California, San Francisco, CA 94158
Michael B. Boffa: Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada
Simone Green: Departments of Medicine, University of California, San Diego, La Jolla, CA
Xiaohong Yang: Departments of Medicine, University of California, San Diego, La Jolla, CA
Edward Dennis: Chemistry, Biochemistry, and Pharmacology, University of California, San Diego, La Jolla, CA
Joseph L. Witztum: Departments of Medicine, University of California, San Diego, La Jolla, CA
Marlys L. Koschinsky: Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada
Sotirios Tsimikas: To whom correspondence should be addressed; Departments of Medicine, University of California, San Diego, La Jolla, CA; To whom correspondence should be addressed

Journal volume & issue: Vol. 54, no. 10
pp. 2815 – 2830

Abstract

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Oxidized phospholipids (OxPLs) are present on apolipoprotein (a) [apo(a)] and lipoprotein (a) [Lp(a)] but the determinants influencing their binding are not known. The presence of OxPLs on apo(a)/Lp(a) was evaluated in plasma from healthy humans, apes, monkeys, apo(a)/Lp(a) transgenic mice, lysine binding site (LBS) mutant apo(a)/Lp(a) mice with Asp55/57→Ala55/57 substitution of kringle (K)IV10)], and a variety of recombinant apo(a) [r-apo(a)] constructs. Using antibody E06, which binds the phosphocholine (PC) headgroup of OxPLs, Western and ELISA formats revealed that OxPLs were only present in apo(a) with an intact KIV10 LBS. Lipid extracts of purified human Lp(a) contained both E06- and nonE06-detectable OxPLs by tandem liquid chromatography-mass spectrometry (LC-MS/MS). Trypsin digestion of 17K r-apo(a) showed PC-containing OxPLs covalently bound to apo(a) fragments by LC-MS/MS that could be saponified by ammonium hydroxide. Interestingly, PC-containing OxPLs were also present in 17K r-apo(a) with Asp57→Ala57 substitution in KIV10 that lacked E06 immunoreactivity. In conclusion, E06- and nonE06-detectable OxPLs are present in the lipid phase of Lp(a) and covalently bound to apo(a). E06 immunoreactivity, reflecting pro-inflammatory OxPLs accessible to the immune system, is strongly influenced by KIV10 LBS and is unique to human apo(a), which may explain Lp(a)’s pro-atherogenic potential.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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