|
| Status |
Public on Aug 26, 2011 |
| Title |
Inhibitory Role of Notch1 in Calcific Aortic Valve Disease |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
|
| Summary |
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 expression Sox9 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.
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| Overall design |
3 samples of aortic valve interstitial cells treated with DAPT were compared with 3 samples of aortic valve interstitial cells treated with DMSO
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| Contributor(s) |
Acharya A, Koenig SN, Galindo CL, Garner HR, Garg V |
| Citation(s) |
22110751 |
| |
| Submission date |
Aug 25, 2011 |
| Last update date |
Jul 31, 2017 |
| Contact name |
Vidu Garg |
| E-mail(s) |
vidu.garg@nationwidechildrens.org
|
| Phone |
614-355-5710
|
| Organization name |
Research Institute at Nationwide Children's Hospital
|
| Department |
Cardiovascular Research
|
| Lab |
Vidu Garg
|
| Street address |
700 Children's Drive WB4239
|
| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43205 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL1355 |
[Rat230_2] Affymetrix Rat Genome 230 2.0 Array |
|
| Samples (6)
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| Relations |
| BioProject |
PRJNA145389 |
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