Oxidized Phospholipids Trigger Atherogenic Inflammation in Murine Arteries

Abstract

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 Ϫ/Ϫ ) 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. Key Words: atherosclerosis Ⅲ oxidized phospholipids Ⅲ inflammation Ⅲ chemokines Ⅲ leukocyte adhesion A therosclerosis is a chronic inflammatory disease involving accumulation of lipoproteins and mononuclear cells in the subendothelial space. Chemokines serve a vital role in supporting the inflammatory response of the arterial wall, leading to atherosclerotic plaque formation. In particular, genetic deletions of monocyte chemotactic protein 1 (MCP-1) or its receptor CCR2, as well as transplantation of bone marrow deficient in the IL-8 receptor homologue CXCR2, [1][2][3] have been shown to decrease monocyte accumulation and lesion formation in mice susceptible to atherosclerosis. Although our knowledge about the mechanisms underlying atherosclerosis and its complications has dramatically increased, the question about the initiating factors or triggers of atherogenesis remains unsolved. Accumulating evidence suggests retention of low-density lipoprotein (LDL) particles in the subendothelial space with subsequent oxidative modification as key steps in beginning atherosclerosis. Oxidized LDL has been shown to induce chemokines such as MCP-1 in vascular cells, but direct evidence from suitable animal models is scarce and it has been questioned if lipoproteins oxidized in vitro yield similar biological responses as lipoproteins oxidized in the arterial wall. 4 Recently, considerable advances have been made in dissecting the molecular components of oxidized LD...

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