Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification. Arterioscler Thromb Vasc Biol 2016 Feb;36(2):328-38
Date
12/05/2015Pubmed ID
26634652Pubmed Central ID
PMC4732913DOI
10.1161/ATVBAHA.115.306091Scopus ID
2-s2.0-84955616856 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
OBJECTIVE: Aortic valve disease, including calcification, affects >2% of the human population and is caused by complex interactions between multiple risk factors, including genetic mutations, the environment, and biomechanics. At present, there are no effective treatments other than surgery, and this is because of the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells within the aortic valve cusps differentiate toward an osteoblast-like cell and deposit bone-like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However, the mechanisms that promote pathological phenotypes in valve interstitial cells are unknown.
APPROACH AND RESULTS: Using a combination of in vitro and in vivo tools with mouse, porcine, and human tissue, we show that in valve interstitial cells, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells. However, in vivo, loss of Tgfβ1 in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease.
CONCLUSIONS: Together, these findings suggest that reduced nuclear localization of Sox9 in valve interstitial cells is an early indicator of calcification, and therefore, pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis.
Author List
Huk DJ, Austin BF, Horne TE, Hinton RB, Ray WC, Heistad DD, Lincoln JAuthor
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Active Transport, Cell NucleusAnimals
Aortic Valve
Aortic Valve Stenosis
Calcinosis
Cells, Cultured
Collagen Type II
Endothelial Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Paracrine Communication
SOX9 Transcription Factor
Signal Transduction
Swine
Time Factors
Tissue Culture Techniques
Transfection
Transforming Growth Factor beta1
rho-Associated Kinases