Preimplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids

Yung Chih Chen, Jennifer Rivera, Melissa Fitzgerald, Christian Hausding, Ya Lan Ying, Xiaowei Wang, Krassimira Todorova, Soren Hayrabedyan, Eytan R. Barnea, Karlheinz Peter

Research output: Contribution to journalArticleResearchpeer-review

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 ApoEdeficient 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.

Original languageEnglish
Pages (from-to)1010-1024
Number of pages15
JournalThrombosis and Haemostasis
Volume115
Issue number5
DOIs
Publication statusPublished - 1 May 2016

Keywords

  • ApoE-deficient mice
  • Atherosclerosis
  • Immune cells
  • Immunomodulatory therapy
  • Macrophage
  • PreImplantation factor (PIF)

Cite this

Chen, Yung Chih ; Rivera, Jennifer ; Fitzgerald, Melissa ; Hausding, Christian ; Ying, Ya Lan ; Wang, Xiaowei ; Todorova, Krassimira ; Hayrabedyan, Soren ; Barnea, Eytan R. ; Peter, Karlheinz. / Preimplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids. In: Thrombosis and Haemostasis. 2016 ; Vol. 115, No. 5. pp. 1010-1024.
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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 ApoEdeficient 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.",
keywords = "ApoE-deficient mice, Atherosclerosis, Immune cells, Immunomodulatory therapy, Macrophage, PreImplantation factor (PIF)",
author = "Chen, {Yung Chih} and Jennifer Rivera and Melissa Fitzgerald and Christian Hausding and Ying, {Ya Lan} and Xiaowei Wang and Krassimira Todorova and Soren Hayrabedyan and Barnea, {Eytan R.} and Karlheinz Peter",
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Chen, YC, Rivera, J, Fitzgerald, M, Hausding, C, Ying, YL, Wang, X, Todorova, K, Hayrabedyan, S, Barnea, ER & Peter, K 2016, 'Preimplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids' Thrombosis and Haemostasis, vol. 115, no. 5, pp. 1010-1024. https://doi.org/10.1160/TH15-08-0640

Preimplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids. / Chen, Yung Chih; Rivera, Jennifer; Fitzgerald, Melissa; Hausding, Christian; Ying, Ya Lan; Wang, Xiaowei; Todorova, Krassimira; Hayrabedyan, Soren; Barnea, Eytan R.; Peter, Karlheinz.

In: Thrombosis and Haemostasis, Vol. 115, No. 5, 01.05.2016, p. 1010-1024.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Preimplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids

AU - Chen, Yung Chih

AU - Rivera, Jennifer

AU - Fitzgerald, Melissa

AU - Hausding, Christian

AU - Ying, Ya Lan

AU - Wang, Xiaowei

AU - Todorova, Krassimira

AU - Hayrabedyan, Soren

AU - Barnea, Eytan R.

AU - Peter, Karlheinz

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