title: PreImplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids.
abstract: PreImplantation factor (PIF) is a 15-amino acid peptide endogenously secreted by viable embryos, regulating/enabling maternal (host) acceptance/tolerance to the "invading" embryo (allograft) all-while preserving maternal immunity to fight infections. Such attributes make PIF a potential therapeutic agent for chronic inflammatory diseases. We investigated whether PIF's immunomodulatory properties prevent progression of atherosclerosis in the hyper-cholesterolaemic ApoE-deficient murine model. Male, high-fat diet fed, ApoE-deficient (ApoE-/-) mice were administered either PBS, scrambled PIF (0.3-3 mg/kg) or PIF (0.3-3 mg/kg) for seven weeks. After treatment, PIF (3 mg/kg)-treated ApoE-/- mice displayed significantly reduced atherosclerosis lesion burden in the aortic sinus and aortic arch, without any effect on lipid profile. PIF also caused a significant reduction in infiltration of macrophages, decreased expression of pro-inflammatory adhesion molecules, cytokines and chemokines in the plaque, and reduced circulating IFN-γ levels. PIF preferentially binds to monocytes/neutrophils. In vitro, PIF attenuated monocyte migration (MCP-1-induced chemotaxis assay) and in vivo in LPS peritonitis model. Also PIF prevented leukocyte extravasation (peritonitis thioglycollate-induced model), demonstrating that PIF exerts its effect in part by modulation of monocyte function. Inhibition of the potassium channel KCNAB3 (Kv1.3) and of the insulin degrading enzyme (IDE) was demonstrated as potential mechanism of PIF's immunomodulatory effects. In conclusion, PIF regulates/lowers inflammation and prevents atherosclerosis development without affecting circulating lipids. Overall our findings establish PIF as a strong immunomodulatory drug candidate for atherosclerosis therapy.
authors: Yung Chih
authors: YC
authors: Chen
authors: Jennifer
authors: J
authors: Rivera
authors: Melissa
authors: M
authors: Fitzgerald
authors: Christian
authors: C
authors: Hausding
authors: Ya-Lan
authors: YL
authors: Ying
authors: Xiaowei
authors: X
authors: Wang
authors: Krassimira
authors: K
authors: Todorova
authors: Soren
authors: S
authors: Hayrabedyan
authors: Eytan R
authors: ER
authors: Barnea
authors: Prof. Karlheinz Peter, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne 8008, Victoria, Australia, Tel.: +61 3 8532 1490, Fax: 61 3 8532 1110, E-mail: karlheinz.peter@bakeridi.edu.au.
authors: Karlheinz
authors: K
authors: Peter
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007339:Insulysin / Q000037:antagonists & inhibitors / Q000235:genetics; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D007155:Immunologic Factors; D018836:Inflammation Mediators; C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D008055:Lipids; D010455:Peptides; D034741:RNA, Small Interfering; C569738:preimplantation factor, synthetic; D007339:Insulysin
keywords: ApoE-deficient mice; Atherosclerosis; PreImplantation Factor (PIF); immune cells; immunomodulatory therapy; macrophage