αDefensins induce a post-translational modification of low density lipoprotein (LDL) that promotes atherosclerosis at normal levels of plasma cholesterol

Rami Abu-Fanne, Emad Maraga, Ihab Abd-Elrahman, Aviel Hankin, Galia Blum, Suhair Abdeen, Nuha Hijazi, Douglas B. Cines, Abd Al Roof Higazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Approximately one-half of the patients who develop clinical atherosclerosis have normal or only modest elevations in plasma lipids, indicating that additional mechanisms contribute to pathogenesis. In view of increasing evidence that inflammation contributes to atherogenesis, we studied the effect of human neutrophil α-defensins on low density lipoprotein (LDL) trafficking, metabolism, vascular deposition, and atherogenesis using transgenic mice expressing human α-defensins in their polymorphonuclear leukocytes (Def+/+). Accelerated Def+/+ mice developed α-defensin·LDL complexes that accelerate the clearance of LDL from the circulation accompanied by enhanced vascular deposition and retention of LDL, induction of endothelial cathepsins, increased endothelial permeability to LDL, and the development of lipid streaks in the aortic roots when fed a regular diet and at normal plasma levels of LDL. Transplantation of bone marrow from Def+/+ to WT mice increased LDL clearance, increased vascular permeability, and increased vascular deposition of LDL, whereas transplantation ofWTbone marrow to Def+/+ mice prevented these outcomes. The same outcome was obtained by treating Def+/+ mice with colchicine to inhibit the release of α-defensins. These studies identify a potential new link between inflammation and the development of atherosclerosis.

Original languageAmerican English
Pages (from-to)2777-2786
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number6
DOIs
StatePublished - 5 Feb 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
©2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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