PMID- 26604037 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20220310 IS - 1755-3245 (Electronic) IS - 0008-6363 (Linking) VI - 109 IP - 2 DP - 2016 Feb 1 TI - A CD1d-dependent lipid antagonist to NKT cells ameliorates atherosclerosis in ApoE-/- mice by reducing lesion necrosis and inflammation. PG - 305-17 LID - 10.1093/cvr/cvv259 [doi] AB - AIMS: 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. METHODS AND 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 IFNgamma 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. IFNgamma and lymphocytes were unaffected by the treatment. CONCLUSION: 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. CI - Published on behalf of the European Society of Cardiology. All rights reserved. (c) The Author 2015. For permissions please email: journals.permissions@oup.com. FAU - Li, Yi AU - Li Y AD - 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. FAU - Kanellakis, Peter AU - Kanellakis P AD - Vascular Biology and Atherosclerosis Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, VIC 8008, Australia. FAU - Hosseini, Hamid AU - Hosseini H AD - 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. FAU - Cao, Anh AU - Cao A AD - 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. FAU - Deswaerte, Virginie AU - Deswaerte V AD - 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. FAU - Tipping, Peter AU - Tipping P AD - Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia. FAU - Toh, Ban-Hock AU - Toh BH AD - Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, VIC, Australia. FAU - Bobik, Alex AU - Bobik A AD - 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. FAU - Kyaw, Tin AU - Kyaw T AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151124 PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 RN - 0 (Antigens, CD1d) RN - 0 (Apolipoproteins E) RN - 0 (CD1d antigen, mouse) RN - 0 (Vascular Cell Adhesion Molecule-1) SB - IM MH - Animals MH - Antigens, CD1d/*metabolism MH - Apolipoproteins E/deficiency/metabolism MH - Atherosclerosis/immunology/*metabolism MH - Inflammation/immunology MH - Lymphocyte Activation/immunology MH - Mice, Knockout MH - Natural Killer T-Cells/*cytology MH - Necrosis/genetics/immunology MH - Plaque, Atherosclerotic/pathology MH - Vascular Cell Adhesion Molecule-1/metabolism OTO - NOTNLM OT - ApoE-/- mice OT - Atherosclerosis OT - DPPE-PEG OT - NKT antagonist OT - NKT cells EDAT- 2015/11/26 06:00 MHDA- 2016/12/15 06:00 CRDT- 2015/11/26 06:00 PHST- 2015/04/14 00:00 [received] PHST- 2015/10/29 00:00 [accepted] PHST- 2015/11/26 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - cvv259 [pii] AID - 10.1093/cvr/cvv259 [doi] PST - ppublish SO - Cardiovasc Res. 2016 Feb 1;109(2):305-17. doi: 10.1093/cvr/cvv259. Epub 2015 Nov 24.