title: Notch1 represses osteogenic pathways in aortic valve cells.
abstract: Calcific aortic stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. However, the molecular pathways leading to calcification are poorly understood. We reported two families in which heterozygous mutations in NOTCH1 caused bicuspid aortic valve and severe aortic valve calcification. NOTCH1 is part of a highly conserved signaling pathway involved in cell fate decisions, cell differentiation, and cardiac valve formation. In this study, we examined the mechanism by which NOTCH1 represses aortic valve calcification. Heterozygous Notch1-null (Notch1(+/)(-)) mice had greater than fivefold more aortic valve calcification than age- and sex-matched wildtype littermates. Inhibition of Notch signaling in cultured sheep aortic valve interstitial cells (AVICs) also increased calcification more than fivefold and resulted in gene expression typical of osteoblasts. We found that Notch1 normally represses the gene encoding bone morphogenic protein 2 (Bmp2) in murine aortic valves in vivo and in aortic valve cells in vitro. siRNA-mediated knockdown of Bmp2 blocked the calcification induced by Notch inhibition in AVICs. These findings suggest that Notch1 signaling in aortic valve cells represses osteoblast-like calcification pathways mediated by Bmp2.
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics, University of California, San Francisco, CA 94158, USA. vnigam@ucsd.edu
authors.forename: Vishal
authors.initials: V
authors.lastname: Nigam
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D015398:Signal Transduction
chemical_list: D055396:Bone Morphogenetic Protein 2; D012333:RNA, Messenger; D051881:Receptor, Notch1
references.citation: Bioinformatics. 2007 Apr 15;23(8):1043-5
references.pmid: 17384426
references.citation: Biochem Biophys Res Commun. 2006 Jul 14;345(4):1460-5
references.pmid: 16729972
references.citation: Hum Mol Genet. 2008 Sep 15;17(18):2886-93
references.pmid: 18593716
references.citation: Genes Dev. 2004 Jan 1;18(1):99-115
references.pmid: 14701881
references.citation: Nature. 2005 Sep 8;437(7056):270-4
references.pmid: 16025100
references.citation: Exp Cell Res. 2003 Nov 1;290(2):370-80
references.pmid: 14567994
references.citation: Genes Dev. 1994 Mar 15;8(6):707-19
references.pmid: 7926761
references.citation: Gastroenterology. 2008 Feb;134(2):544-55
references.pmid: 18242220
references.citation: Genes Dev. 2000 Jun 1;14(11):1343-52
references.pmid: 10837027
references.citation: Circulation. 2005 Jun 21;111(24):3316-26
references.pmid: 15967862
references.citation: J Thorac Cardiovasc Surg. 2007 Aug;134(2):290-6
references.pmid: 17662764
references.citation: Nat Neurosci. 2005 Jun;8(6):709-15
references.pmid: 15917835
references.citation: Cell. 1997 May 30;89(5):747-54
references.pmid: 9182762
references.citation: Stem Cells. 2008 Mar;26(3):715-23
references.pmid: 18055449
references.citation: Arch Neurol. 2008 Aug;65(8):1031-8
references.pmid: 18695053
references.citation: Circulation. 2006 Nov 7;114(19):2065-9
references.pmid: 17075015
references.citation: Gastroenterology. 2008 Jan;134(1):131-44
references.pmid: 18166351
references.citation: Circulation. 2001 Mar 20;103(11):1522-8
references.pmid: 11257079
references.citation: J Cell Sci. 2004 Mar 1;117(Pt 7):1269-80
references.pmid: 14996946
references.citation: Circ Res. 2006 Jun 23;98(12):1471-8
references.pmid: 16690879
references.citation: Nat Biotechnol. 2008 Oct;26(10):1169-78
references.pmid: 18820686
references.citation: Nat Genet. 2003 Mar;33(3):416-21
references.pmid: 12590261
references.citation: Cell Stem Cell. 2008 Mar 6;2(3):219-29
references.pmid: 18371447
references.citation: Nat Immunol. 2004 Mar;5(3):247-53
references.pmid: 14985712
references.citation: J Heart Valve Dis. 2004 Jul;13(4):560-6
references.pmid: 15311861
references.citation: Endocrinology. 2003 Dec;144(12):5631-9
references.pmid: 12960086
references.citation: Nature. 2003 May 22;423(6938):409-14
references.pmid: 12717450
references.citation: Circulation. 1994 Aug;90(2):844-53
references.pmid: 7519131
references.citation: Endocrinology. 2008 Aug;149(8):3890-9
references.pmid: 18420737
references.citation: Development. 2006 Nov;133(21):4381-90
references.pmid: 17021042
references.citation: J Clin Invest. 2005 May;115(5):1210-20
references.pmid: 15841209
references.citation: Circulation. 2006 Jul 4;114(1 Suppl):I547-52
references.pmid: 16820635
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: J Bone Miner Res. 2004 Jun;19(6):947-58
references.pmid: 15125793
references.citation: J Am Coll Cardiol. 1994 Apr;23(5):1162-70
references.pmid: 8144784
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Circulation. 2006 Feb 14;113(6):e85-151
references.pmid: 16407573
references.citation: Heart. 2002 Oct;88(4):348-51
references.pmid: 12231589
references.citation: Circulation. 2003 May 6;107(17):2181-4
references.pmid: 12719282
references.citation: Dev Biol. 1999 Dec 1;216(1):72-84
references.pmid: 10588864
references.citation: Ann Thorac Surg. 2003 Feb;75(2):457-65; discussion 465-6
references.pmid: 12607654
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Circulation. 2005 Aug 30;112(9 Suppl):I229-34
references.pmid: 16159822