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Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves - association with low BMP antagonists and SMAD6
- Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves - association with low BMP antagonists and SMAD6
- Ankeny R.F.; Thourani V.H.; Weiss D.; Vega J.D.; Taylor W.R.; Nerem R.M.; Jo H.
- Ewha Authors
- Issue Date
- Journal Title
- PLoS ONE
- PLoS ONE vol. 6, no. 6
- SCIE; SCOPUS
- Document Type
- Background: Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. Methods and Results: Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFβ pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium. Conclusions: SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs. © 2011 Ankeny et al.
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