Inhibitory role of Notch1 in calcific aortic valve disease

PLoS One. 2011;6(11):e27743. doi: 10.1371/journal.pone.0027743. Epub 2011 Nov 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Aortic Valve / metabolism*
  • Aortic Valve / pathology
  • COS Cells
  • Calcinosis / metabolism*
  • Calcinosis / pathology
  • Cell Cycle Proteins / metabolism
  • Chlorocebus aethiops
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation
  • Heart Valve Diseases / metabolism*
  • Heart Valve Diseases / pathology
  • Humans
  • Middle Aged
  • Protein Transport
  • Rats
  • Receptor, Notch1 / metabolism*
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction
  • Swine
  • Transcription, Genetic


  • Cell Cycle Proteins
  • Extracellular Matrix Proteins
  • Receptor, Notch1
  • SOX9 Transcription Factor