Published online before print December 9, 2004, doi: 10.1161/01.ATV.0000153106.03644.a0
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Oxidized Phospholipids Trigger Atherogenic Inflammation in Murine Arteries
From the Department of Vascular Biology and Thrombosis Research (A.F., V.N.B., G.K., A.K., B.R.B., N.L.), University of Vienna, Austria; Wilheminen Hospital (A.F.), Vienna, Austria; the Department of Cardiovascular Molecular Biology (A.S., C.W.), University of Aachen, Germany; and the Cardiology Research Center (P.B.), Moscow, Russia.
Correspondence to Norbert Leitinger, Cardiovascular Research Center, University of Virginia, PO Box 801394, Charlottesville, VA 22908. E-mail nl2q{at}virginia.edu
Objective— Lipoprotein-derived phospholipid oxidation products have been implicated as candidate triggers of the inflammatory process in atherosclerosis. However, in vivo evidence regarding the impact of oxidized phospholipids on the artery wall thus far has been elusive. Therefore, the aim of this study was to investigate if structurally defined oxidized phospholipids induce expression of atherogenic chemokines and monocyte adhesion in intact murine arteries.
Methods and Results— To model the accumulation of oxidized phospholipids in the arterial wall, oxidized 1-palmitoyl-2-arachidonoyl-sn-3-glycero-phosphorylcholine (OxPAPC) was topically applied to carotid arteries in mice using pluronic gel. Using quantitative reverse-transcriptase polymerase chain reaction (PCR) and immunohistochemistry, we show that OxPAPC induced a set of atherosclerosis-related genes, including monocyte chemotactic protein 1 (MCP-1) and keratinocyte-derived chemokine (KC), tissue factor (TF), interleukin 6 (IL-6), heme oxygenase 1 (HO-1), and early growth response 1 (EGR-1). OxPAPC-regulated chemokines were also expressed in atherosclerotic lesions of apolipoprotein E-deficient (ApoE–/–) mice. In isolated perfused carotid arteries, OxPAPC triggered rolling and firm adhesion of monocytes in a P-selectin and KC-dependent manner.
Conclusion— Oxidized phospholipids contribute to vascular inflammation in murine arteries in vivo, initiating atherogenic chemokine expression that leads to monocyte adhesion; therefore, they can be regarded as triggers of the inflammatory process in atherosclerosis.
Oxidized phospholipids have been implied to play a role in atherogenesis; however, whether they trigger vascular inflammation in vivo is not known. Using a novel experimental approach, we demonstrate that oxidized phospholipids elicit atherogenic inflammation in murine arteries in vivo, implicating oxidized phospholipids as triggers of vascular inflammation.
Key Words: atherosclerosis • oxidized phospholipids • inflammation • chemokines • leukocyte adhesion
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