title: A CD1d-dependent lipid antagonist to NKT cells ameliorates atherosclerosis in ApoE-/- mice by reducing lesion necrosis and inflammation.
abstract: OBJECTIVE
  Atherosclerosis-related deaths from heart attacks and strokes remain leading causes of global mortality, despite the use of lipid-lowering statins. Thus, there is an urgent need to develop additional therapies.
  
  
  RESULTS
  Reports that NKT cells promote atherosclerosis and an NKT cell CD1d-dependent lipid antagonist (DPPE-PEG350, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethyleneglycol)-350]) reduces allergen-induced inflammation led us to investigate its therapeutic potential in preventing the development and progression of experimental atherosclerosis. DPPE-PEG350 was administered to hyperlipidaemic ApoE(-/-) mice with/without established atherosclerosis. Atherosclerosis and immune cells were assessed in the aortic sinus lesions. Lesion expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) responsible for inflammatory immune cell recruitment as well as mRNA expression of IFNγ and its plasma levels were investigated. Necrotic cores and lesion smooth muscle and collagen contents important in plaque stability were determined as were plasma lipid levels. DPPE-PEG350 reduced atherosclerosis development and delayed progression of established atherosclerosis without affecting plasma lipids. CD4 and CD8 T cells and B cells in atherosclerotic lesions were decreased in DPPE-PEG350-treated mice. Lesion MCP-1 and VCAM-1 protein expression and necrotic core size were reduced without affecting lesion smooth muscle and collagen content. IFNγ and lymphocytes were unaffected by the treatment.
  
  
  CONCLUSIONS
  The attenuation of progression of established atherosclerosis together with reduced development of atherosclerosis in hyperlipidaemic mice by the NKT antagonist, without affecting NKT cell or other lymphocyte numbers, suggests that targeting lesion inflammation via CD1d-dependent activation of NKT cells using DPPE-PEG350 has a therapeutic potential in treating atherosclerosis.
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia.
authors.forename: Hamid
authors.initials: H
authors.lastname: Hosseini
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia.
authors.forename: Anh
authors.initials: A
authors.lastname: Cao
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, VIC, Australia.
authors.forename: Virginie
authors.initials: V
authors.lastname: Deswaerte
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Tipping
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia.
authors.forename: Ban-Hock
authors.initials: BH
authors.lastname: Toh
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, VIC, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia tinsoe.kyaw@bakeridi.edu.au.
authors.forename: Tin
authors.initials: T
authors.lastname: Kyaw
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology*; D009336:Necrosis / Q000235:genetics / Q000276:immunology; D058226:Plaque, Atherosclerotic / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D001057:Apolipoproteins E; C584692:CD1d antigen, mouse; D019010:Vascular Cell Adhesion Molecule-1
keywords: ApoE−/− mice; Atherosclerosis; DPPE-PEG; NKT antagonist; NKT cells