title: Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-κB activation.
abstract: OBJECTIVE
  Calcific aortic valve disease is a leading cardiovascular disease in the elderly, and progressive calcification results in the failure of valvular function. Aortic valve interstitial cells (AVICs) from stenotic valves express higher levels of bone morphogenetic protein-2 in response to Toll-like receptor 4 stimulation. We recently found that Toll-like receptor 4 interacts with Notch1 in human AVICs. This study tests the hypothesis that Notch1 promotes the pro-osteogenic response of human AVICs.
  
  
  RESULTS
  AVICs isolated from diseased human valves expressed higher levels of bone morphogenetic protein-2 and alkaline phosphatase after lipopolysaccharide stimulation. The augmented pro-osteogenic response is associated with elevated cellular levels of Notch1 and enhanced Notch1 cleavage in response to lipopolysaccharide stimulation. Inhibition or silencing of Notch1 suppressed the pro-osteogenic response in diseased cells, and the Notch 1 ligand, Jagged1, enhanced the response in AVICs isolated from normal human valves. Interestingly, extracellular signal-regulated protein kinases 1/2 (ERK1/2) and nuclear factor-κB phosphorylation induced by lipopolysaccharide was markedly reduced by inhibition or silencing of Notch1 and enhanced by Jagged1. Inhibition of ERK1/2 or nuclear factor-κB also reduced bone morphogenetic protein-2 and alkaline phosphatase expression induced by lipopolysaccharide.
  
  
  CONCLUSIONS
  Notch1 mediates the pro-osteogenic response to Toll-like receptor 4 stimulation in human AVICs. Elevated Notch1 levels and enhanced Notch1 activation play a major role in augmentation of the pro-osteogenic response of AVICs of stenotic valves through modulation of ERK1/2 and nuclear factor-κB activation. These pathways could be potential therapeutic targets for prevention of the progression of calcific aortic valve disease.
authors: Department of Surgery, University of Colorado Denver, Aurora, CO, USA.
authors: Qingchun
authors: Q
authors: Zeng
authors: Rui
authors: R
authors: Song
authors: Lihua
authors: L
authors: Ao
authors: Michael J
authors: MJ
authors: Weyant
authors: Joon
authors: J
authors: Lee
authors: Dingli
authors: D
authors: Xu
authors: David A
authors: DA
authors: Fullerton
authors: Xianzhong
authors: X
authors: Meng
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D001021:Aortic Valve / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002114:Calcinosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C440499:lipopolysaccharide, Escherichia coli O111 B4; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000469:Alkaline Phosphatase
keywords: Notch1; Toll-like receptor 4; aortic valve; pro-osteogenic proteins; signal transduction
references: J Biol Chem. 2011 May 27;286(21):19138-48
references: 21471203
references: J Cell Physiol. 2010 Apr;223(1):168-77
references: 20049872
references: Eur J Immunol. 2008 Jan;38(1):174-83
references: 18085664
references: Circulation. 2007 Jun 12;115(23):2948-56
references: 17533181
references: Dev Cell. 2009 May;16(5):633-47
references: 19460341
references: Eur J Immunol. 2009 Sep;39(9):2556-70
references: 19662631
references: J Proteome Res. 2010 Nov 5;9(11):5913-21
references: 20825172
references: Glia. 2008 Aug 15;56(11):1224-37
references: 18449946
references: Ann Thorac Surg. 2004 Feb;77(2):537-43
references: 14759434
references: J Biol Chem. 2010 Oct 22;285(43):33485-33498
references: 20710027
references: Circulation. 2012 Sep 11;126(11 Suppl 1):S222-30
references: 22965987
references: J Biol Chem. 2005 Apr 22;280(16):15842-8
references: 15695512
references: Oral Microbiol Immunol. 2009 Feb;24(1):64-8
references: 19121072
references: J Biol Chem. 2011 Apr 8;286(14):12213-20
references: 21325271
references: Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1104-11
references: 19407244
references: J Bone Miner Res. 2012 Mar;27(3):538-51
references: 22072425
references: J Bone Miner Res. 2002 Feb;17(2):231-9
references: 11811553
references: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3356-65
references: 17921324
references: Nature. 2005 Sep 8;437(7056):270-4
references: 16025100
references: Circulation. 2001 Mar 20;103(11):1522-8
references: 11257079
references: Atherosclerosis. 2003 Oct;170(2):205-11
references: 14612199
references: J Mol Cell Cardiol. 2009 Dec;47(6):828-34
references: 19695258
references: Int J Cardiol. 2012 Jun 28;158(1):18-25
references: 21247641
references: Circulation. 2006 Jul 4;114(1 Suppl):I547-52
references: 16820635
references: Ann Thorac Surg. 2008 Jul;86(1):71-6
references: 18573401
references: J Am Coll Cardiol. 2009 Feb 10;53(6):491-500
references: 19195606
references: Circulation. 2011 Oct 18;124(16):1783-91
references: 22007101
references: Heart. 2003 Jul;89(7):801-5
references: 12807865
references: Am J Physiol Cell Physiol. 2008 Jan;294(1):C29-35
references: 17942642
references: Circ Res. 2011 May 27;108(11):1381-91
references: 21617135
references: J Heart Valve Dis. 1999 May;8(3):254-60
references: 10399657