Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 5, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp081
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The role of the scavenger receptor CD36 in regulating mononuclear phagocyte trafficking to atherosclerotic lesions and vascular inflammation
1 Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada
2 Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
3 Department of Cell Biology, Lerner Research Institute, Cleveland, OH, USA
* Corresponding authors: Faculty of Pharmacy, Université de Montréal, P.O.Box 6128, Station Centre-Ville, Montréal, Québec, Canada H3C 3J7. Tel: +1 514 343 7110; fax: +1 514 343 2102; E-mail address: sylvie.marleau{at}umontreal.ca or huy.ong{at}umontreal.ca
Aims: CD36 has been shown to associate with nonreceptor Src kinases to activate mitogen-activated protein (MAP) kinases and trigger cytoskeletal remodelling, important events in foam cell formation and macrophage migration. Yet, its role in regulating circulating mononuclear phagocyte trafficking to atherosclerotic lesions has not been investigated. The aim of the present study was to investigate the role of CD36 in modulating the recruitment of mononuclear phagocytes to the arterial wall and the associated vascular inflammation, using both pharmacological and genetic approaches.
Methods and results: Apolipoprotein E-deficient (apoE-/-) mice fed a high-fat, high-cholesterol diet were treated daily with a CD36 ligand, EP 80317 (300 µg/kg), or 0.9% NaCl for 6 or 12 weeks. Forty-eight hours before sacrifice, mice were injected i.v. with 111Indium-labelled macrophages. A 65% (P<0.001) reduction of labelled macrophage accumulation at aortic lesions was observed in EP 80317-treated mice, mainly at the level of the aortic arch and iliac arteries, correlating with a 43% reduction of atherosclerotic lesion areas. This was associated with reduced phosphorylation of the focal adhesion kinase Pyk2 following stimulation with oxidised phospholipid in a Src kinases- and CD36-dependent manner. At the vascular level, EP 80317 treatment reduced the expression of pro-inflammatory proteins, including NADPH oxidase, inducible nitric oxide synthase (iNOS), vascular endothelial cell adhesion molecule-1 (VCAM-1) and CCL2 chemokine. Plasma IL-6 levels were also reduced by 40% (P<0.05). In contrast, none of these proteins were modulated in EP 80317-treated apoE/CD36 double knockout (apoE-/-/CD36-/-) mice.
Conclusions: Our results support a role for CD36 signalling in the regulation of mononuclear phagocyte trafficking to atherosclerotic-prone sites and in the associated vascular wall inflammation.
Time for primary review: 30 Days
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Cardiovasc Res 2009 83: 5-6.
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