Inhibitory role of Notch1 in calcific aortic valve disease

Asha Acharya, Chetan P. Hans, Sara N. Koenig, Haley A. Nichols, Cristi L. Galindo, Harold R. Garner, Walter H. Merrill, Robert B. Hinton, Vidu Garg

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Aortic 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.

Original languageEnglish (US)
Article numbere27743
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 16 2011

Fingerprint

Aortic Diseases
calcification
Aortic Valve
Swine
Cartilage
Heart Valve Diseases
swine
Critical Pathways
Gene expression
heart diseases
heart valve diseases
Rats
cartilage
cell differentiation
Transcription Factors
Genes
Cell Differentiation
Calcium
Down-Regulation
transcription factors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Acharya, A., Hans, C. P., Koenig, S. N., Nichols, H. A., Galindo, C. L., Garner, H. R., ... Garg, V. (2011). Inhibitory role of Notch1 in calcific aortic valve disease. PLoS One, 6(11), [e27743]. https://doi.org/10.1371/journal.pone.0027743

Inhibitory role of Notch1 in calcific aortic valve disease. / Acharya, Asha; Hans, Chetan P.; Koenig, Sara N.; Nichols, Haley A.; Galindo, Cristi L.; Garner, Harold R.; Merrill, Walter H.; Hinton, Robert B.; Garg, Vidu.

In: PLoS One, Vol. 6, No. 11, e27743, 16.11.2011.

Research output: Contribution to journalArticle

Acharya, A, Hans, CP, Koenig, SN, Nichols, HA, Galindo, CL, Garner, HR, Merrill, WH, Hinton, RB & Garg, V 2011, 'Inhibitory role of Notch1 in calcific aortic valve disease', PLoS One, vol. 6, no. 11, e27743. https://doi.org/10.1371/journal.pone.0027743
Acharya A, Hans CP, Koenig SN, Nichols HA, Galindo CL, Garner HR et al. Inhibitory role of Notch1 in calcific aortic valve disease. PLoS One. 2011 Nov 16;6(11). e27743. https://doi.org/10.1371/journal.pone.0027743
Acharya, Asha ; Hans, Chetan P. ; Koenig, Sara N. ; Nichols, Haley A. ; Galindo, Cristi L. ; Garner, Harold R. ; Merrill, Walter H. ; Hinton, Robert B. ; Garg, Vidu. / Inhibitory role of Notch1 in calcific aortic valve disease. In: PLoS One. 2011 ; Vol. 6, No. 11.
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