title: Milk-derived bioactive peptides inhibit human endothelial-monocyte interactions via PPAR-γ dependent regulation of NF-κB.
abstract: BACKGROUND
  Milk-derived bioactive peptides retain many biological properties and have therapeutic effects in cardiovascular disorders such as atherosclerosis. Under inflammatory conditions the expression of endothelial cells adhesion molecules is induced, increasing monocyte adhesion to human vessel wall, a critical step in the pathogenesis of atherosclerosis. In the present work we explored the effects of milk-derived bioactive peptides on the expression of the inflammatory phenotype of human endothelial cells and their effects on monocyte adherence to endothelial cells.
  
  
  RESULTS
  Treatment of endothelial cells with milk-derived hydrolysate inhibited their production of inflammatory proteins MCP-1 and IL-8 and expression of VCAM-1, ICAM-1 and E-selectin. Milk derived hydrolysate also attenuated the adhesion of human monocytes to activated endothelial cells. The effect was similar to that obtained in endothelial cells treated with troglitazone, a ligand of peroxisome proliferators-activator receptor-gamma (PPAR-γ). PPAR-γ is a transcription factor which when activated antagonises the pro-inflammatory capability of nuclear factor κB (NF-κB). We further examined whether the effects of milk-derived hydrolysates on endothelial cells may be mediated through NF-κB activation via a PPAR-γ dependent mechanism. The specific PPAR-γ inhibitor, GW9662 blocked the effects of the hydrolysate on the NF-κB-mediated chemokines and adhesion molecules expression in endothelial cells.
  
  
  CONCLUSIONS
  These results suggest that milk-derived bioactive peptides work as anti-atherogenic agents through the inhibition of endothelial-dependent adhesive interactions with monocytes by inhibiting the NF-κB pathway through a PPAR-γ dependent mechanism.
authors: FHI, Food for Health Ireland, University College Dublin, Dublin, Ireland ; School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, 4 Ireland.
authors: Simone
authors: S
authors: Marcone
authors: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors: Karen
authors: K
authors: Haughton
authors: Teagasc, Biotechnology Centre, Moorepark, Fermoy, County Cork Ireland.
authors: Paul J
authors: PJ
authors: Simpson
authors: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors: Orina
authors: O
authors: Belton
authors: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, 4 Ireland.
authors: Desmond J
authors: DJ
authors: Fitzgerald
keywords: Atherosclerosis; Inflammation; Milk-derived bioactive peptides; NF-κB; PPAR-γ
references: Am J Clin Nutr. 1996 Nov;64(5):767-71
references: 8901799
references: J Physiol Pharmacol. 2001 Dec;52(4 Pt 2):745-54
references: 11785770
references: Diabetes Care. 2001 Feb;24(2):392-7
references: 11213897
references: Lipids. 2010 Oct;45(10):925-39
references: 20397059
references: J Dairy Res. 2004 Feb;71(1):51-7
references: 15068067
references: J Nutr. 2003 Jul;133(7):2326-30
references: 12840201
references: Nahrung. 1999 Jun;43(3):190-5
references: 10399353
references: Nat Rev Immunol. 2002 Oct;2(10):748-59
references: 12360213
references: Comp Biochem Physiol C. 1990;96(2):367-71
references: 1980446
references: Curr Mol Med. 2001 Dec;1(6):633-53
references: 11899253
references: Circ Res. 2007 Aug 3;101(3):234-47
references: 17673684
references: Curr Opin Biotechnol. 2007 Apr;18(2):163-9
references: 17292602
references: Postgrad Med J. 1991;67 Suppl 5:S38-40
references: 1839438
references: Food Chem. 2014 Dec 15;165:129-33
references: 25038658
references: Food Chem Toxicol. 1996 Jan;34(1):131-45
references: 8603791
references: Circulation. 2000 Jan 25;101(3):235-8
references: 10645917
references: Circulation. 2007 Mar 13;115(10):1285-95
references: 17353456
references: J Dairy Sci. 1987 Feb;70(2):230-42
references: 3571630
references: J Dairy Res. 1997 May;64(2):207-19
references: 9161914
references: Curr Pharm Des. 2003;9(16):1289-95
references: 12769737
references: Br J Nutr. 2000 Nov;84 Suppl 1:S155-9
references: 11242460
references: Circulation. 1997 Dec 16;96(12 ):4219-25
references: 9416885
references: J Biol Chem. 1999 Oct 22;274(43):30353-6
references: 10521409
references: J Atheroscler Thromb. 2011;18(5):351-8
references: 21427505
references: Antimicrob Agents Chemother. 2001 Aug;45(8):2309-15
references: 11451690
references: Biofactors. 2004;21(1-4):55-61
references: 15630170
references: J Hypertens. 1996 Oct;14(10):1215-21
references: 8906521
references: Hypertens Res. 2007 Jun;30(6):489-96
references: 17664851
references: Reprod Nutr Dev. 2002 Sep-Oct;42(5):433-59
references: 12537255
references: Nature. 2000 Jan 6;403(6765):103-8
references: 10638762
references: J Dairy Res. 1998 Aug;65(3):401-11
references: 9718493
references: J Immunol. 2012 Jul 1;189(1):365-72
references: 22623332
references: Cell. 1995 Dec 15;83(6):835-9
references: 8521507
references: J Dairy Sci. 1996 Aug;79(8):1316-21
references: 8880454
references: Curr Pharm Des. 2011 Dec;17(37):4089-110
references: 22204371
references: Biochem Biophys Res Commun. 2001 Apr 6;282(3):717-22
references: 11401521
references: Curr Pharm Des. 2007;13(8):829-43
references: 17430184
references: Biopolymers. 1997;43(2):119-28
references: 9216247
references: J Physiol Pharmacol. 2009 Dec;60(4):11-20
references: 20065492
references: Lancet. 1998 Jan 10;351(9096):88-92
references: 9439492
references: Eur J Clin Nutr. 2010 Apr;64(4):424-31
references: 20145666
references: Br J Nutr. 1995 Apr;73(4):583-90
references: 7794873
references: J Nutr. 1996 Dec;126(12):3063-8
references: 9001375
references: J Immunol. 2012 Jul 1;189(1):411-24
references: 22661092
references: Adv Food Nutr Res. 2003;47:175-276
references: 14639784
references: J Immunol. 2010 Sep 15;185(6):3718-27
references: 20709957
references: J Nutr. 2006 Aug;136(8):2148-52
references: 16857833
references: Antioxid Redox Signal. 2008 Sep;10(9):1631-74
references: 18598143
references: J Nutr. 2013 Jul;143(7):1109-14
references: 23658425
references: Inflamm Res. 2000 Oct;49(10):497-505
references: 11089900
references: Food Funct. 2011 Apr;2(3-4):153-67
references: 21779574
references: N Engl J Med. 1997 Apr 17;336(16):1117-24
references: 9099655
references: Int J Immunopathol Pharmacol. 2011 Oct-Dec;24(4):817-25
references: 22230389
references: Shock. 2011 Sep;36(3):228-34
references: 21617575
references: Biochem Pharmacol. 2000 Oct 15;60(8):1245-50
references: 11007963
references: BMC Physiol. 2005 Feb 06;5(1):3
references: 15694007
references: J Am Coll Nutr. 2009 Feb;28 Suppl 1:91S-102S
references: 19571167
references: Biochemistry. 1999 Sep 28;38(39):12959-68
references: 10504268
references: J Dairy Sci. 1994 Apr;77(4):917-22
references: 8201050
references: Biochem Biophys Res Commun. 2001 Feb 16;281(1):57-62
references: 11178960
references: Arterioscler Thromb Vasc Biol. 1999 Sep;19(9):2094-104
references: 10479650
references: Curr Drug Targets. 2000 Dec;1(4):387-99
references: 11467077
references: Mol Immunol. 2012 Feb;50(1-2):117-23
references: 22264835
references: Trends Cardiovasc Med. 2008 Aug;18(6):228-32
references: 19185814
references: Biotechnol J. 2007 Apr;2(4):435-49
references: 17407211
references: J Biol Chem. 2003 Dec 19;278(51):51251-60
references: 14532268