title: α-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol.
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 of WT bone 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.
authors.affiliation: From the Department of Clinical Biochemistry and.
authors.forename: Rami
authors.identifier: http://orcid.org/0000-0003-4851-3780
authors.initials: R
authors.lastname: Abu-Fanne
authors.affiliation: From the Department of Clinical Biochemistry and.
authors.forename: Emad
authors.initials: E
authors.lastname: Maraga
authors.affiliation: the School of Pharmacy, Hadassah-Hebrew University, Jerusalem IL-91120, Israel and.
authors.forename: Ihab
authors.initials: I
authors.lastname: Abd-Elrahman
authors.affiliation: From the Department of Clinical Biochemistry and.
authors.forename: Aviel
authors.initials: A
authors.lastname: Hankin
authors.affiliation: the School of Pharmacy, Hadassah-Hebrew University, Jerusalem IL-91120, Israel and.
authors.forename: Galia
authors.initials: G
authors.lastname: Blum
authors.affiliation: From the Department of Clinical Biochemistry and.
authors.forename: Suhair
authors.initials: S
authors.lastname: Abdeen
authors.affiliation: From the Department of Clinical Biochemistry and.
authors.forename: Nuha
authors.initials: N
authors.lastname: Hijazi
authors.affiliation: the Department of Pathology and Laboratory Medicine, Perelman School of Medicine-University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.affiliation: From the Department of Clinical Biochemistry and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine-University of Pennsylvania, Philadelphia, Pennsylvania 19104 higazi@mail.med.upenn.edu.
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics / Q000473:pathology; D002403:Cathepsins / Q000097:blood / Q000235:genetics; D002784:Cholesterol / Q000097:blood* / Q000235:genetics; D003078:Colchicine / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000473:pathology; D008077:Lipoproteins, LDL / Q000097:blood* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000097:blood / Q000235:genetics; D011499:Protein Processing, Post-Translational; D023084:alpha-Defensins / Q000097:blood* / Q000235:genetics
chemical_list: D008077:Lipoproteins, LDL; D046912:Multiprotein Complexes; D023084:alpha-Defensins; D002784:Cholesterol; D002403:Cathepsins; D003078:Colchicine
keywords: atherosclerosis; defensin; lipoprotein; low density lipoprotein (LDL); neutrophil; α-defensins