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Study design: Other. Population: Calcific Aortic Valve Disease (n=7). Intervention: Notch signaling inhibition (DAPT) vs. DMSO (vehicle control). Primary outcome: Aortic valve calcification and Sox9 expression.

November 16, 2011PLoS ONE113 citationsOpen Access

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

AAAsha Acharya CHChetan P. Hans SKSara N. Koenig

Key Result

Inhibition of Notch signaling accelerated aortic valve calcification in vitro, a process that was attenuated by the addition of Sox9, demonstrating a Sox9-dependent mechanism.

PICO

Population

Translational study utilizing human calcific aortic valve specimens (n=7, mean age 64 years) alongside rat and porcine in vitro models to investigate Notch1 signaling.

Intervention / Comparator

Notch signaling inhibition (DAPT) vs DMSO (vehicle control) (10 µM)

Primary Outcome

Aortic valve calcification and Sox9 expression

Limitations

In vitro model systems may not fully replicate in vivo human disease progression
Rat aortic valve interstitial cells require osteogenic media to calcify, unlike porcine cells

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.

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