The role of the scavenger receptor CD36 in regulating mononuclear phagocyte trafficking to atherosclerotic lesions and vascular inflammation.
OBJECTIVE
CD36 has been shown to associate with non-receptor Src kinases to activate mitogen-activated protein 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.


RESULTS
Apolipoprotein E-deficient (apoE(-/-)) mice fed a high-fat, high-cholesterol diet were treated daily with a CD36 ligand, EP 80317 (300 microg/kg), or 0.9% NaCl for 6 or 12 weeks. Forty-eight hours before sacrifice, mice were injected iv with (111)Indium-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 oxidized phospholipid in a Src kinase- 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, vascular endothelial cell adhesion molecule-1, and CCL2 chemokine. Plasma IL-6 levels were also reduced by 40% (P < 0.05). In contrast, none of these proteins was 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.
Harb
Diala
D
Faculty of Pharmacy, Université de Montréal, Station Centre-Ville, Montréal, QC, Canada.
Bujold
Kim
K
Febbraio
Maria
M
Sirois
Martin G
MG
Ong
Huy
H
Marleau
Sylvie
S
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D010586:Phagocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010742:Phospholipid Ethers / Q000494:pharmacology; D051116:Receptors, Scavenger / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014657:Vasculitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019061:src-Family Kinases / Q000378:metabolism
C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D001057:Apolipoproteins E; D018955:CD36 Antigens; C468852:EP80317; D008077:Lipoproteins, LDL; D009842:Oligopeptides; D010742:Phospholipid Ethers; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D019061:src-Family Kinases