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.
Highlights
Valvular heart disease is responsible for over 20,000 deaths each year in the United States alone, and the aortic valve is the most commonly affected, afflicting an estimated 2.5 percent of adults [1,2]
aortic valvular interstitial cells (AVICs) disarray was demonstrated in all aspects of the interstitium, and clusters of AVICs were seen in proximity to areas of early mineralization (Figure 2C) and overt calcification (Figure 2D)
Evidence of calcification was confirmed by von Kossa and Alizarin red staining. These findings demonstrate that calcific aortic valve disease (CAVD) is characterized by heterogenous disruption of extracellular matrix (ECM) and AVIC organization, suggesting molecular mechanisms that regulate calcification processes may do so in a spatially restricted manner
Summary
Valvular heart disease is responsible for over 20,000 deaths each year in the United States alone, and the aortic valve is the most commonly affected, afflicting an estimated 2.5 percent of adults [1,2]. In vitro model systems using aortic valvular interstitial cells (AVICs) that display osteoblast-like characteristics have provided major insights into the mechanistic basis of calcific valve disease [7]. In addition to the AVICs and overlying endothelial cells, mature adult valves contain a highly diversified and dynamic extracellular matrix (ECM) that exhibits many structural and regulatory characteristics of connective tissues, such as those observed in developing cartilage, tendon and bone [8]. A key transcriptional regulator implicated in this process is Sox, which is expressed in the developing endocardial cushions and mature valves and when deleted in mice results in valve malformation and calcification [11,12,13]. The molecular pathways that regulate Sox in valve calcification remain unknown
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