Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

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dc.contributorVirginia Techen
dc.contributor.authorAcharya, Ashaen
dc.contributor.authorHans, Chetan P.en
dc.contributor.authorKoenig, Sara N.en
dc.contributor.authorNichols, Haley A.en
dc.contributor.authorGalindo, Cristi L.en
dc.contributor.authorGarner, Harold R.en
dc.contributor.authorMerrill, Walter H.en
dc.contributor.authorHinton, Robert B.en
dc.contributor.authorGarg, Viduen
dc.date.accessed2014-04-03en
dc.date.accessioned2014-04-09T15:07:20Zen
dc.date.available2014-04-09T15:07:20Zen
dc.date.issued2011-11-16en
dc.description.abstractAortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.en
dc.description.sponsorshipThis work was supported in part by a grant (U54 AI057156) to C.L.G and H.R.G. from NIH/NIAID. A.A. is supported by an American Heart Association-Texas affiliate postdoctoral fellowship, C.L.G. is supported by an NIH cardiology fellowship, R.B.H. is supported by a grant from NIH/NHLBI (K23 HL085122), and V.G. is supported by grants from the NIH/NHLBI (R01 HL088965) and Children’s Heart Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of manuscript.en
dc.identifier.citationA. Acharya CPH S.N. Koenig H.A. Nichols C.L. Galindo H. R Garner W.H. Merrill R. B. Hinton and V. Garg. Inhibitory Role of Notch1 in Calcific Aortic Valve Disease. PLoS ONE. 2011.en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0027743en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://hdl.handle.net/10919/47003en
dc.identifier.urlhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027743en
dc.language.isoen_USen
dc.publisherPLoS ONEen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectAgeden
dc.subjectCOS Cellsen
dc.subjectAortic Valve/metabolismen
dc.titleInhibitory Role of Notch1 in Calcific Aortic Valve Diseaseen
dc.title.serialPLoS Oneen
dc.typeArticle - Refereeden

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