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Author Notes:

E-mail: hjo@bme.gatech.edu

Conceived and designed the experiments: RFA HJ RMN VHT.

Performed the experiments: RFA VHT.

Analyzed the data: RFA HJ RMN VHT.

Contributed reagents/materials/analysis tools: RFA HJ RMN VHT DW WRT JDV.

Wrote the paper: RFA HJ RMN VHT.

Authors would like to recognize Casey J. Holliday and Sarah Gerbig in contributing to the content of this manuscript.

The authors have declared that no competing interests exist.


Research Funding:

This work was supported by funding from National Institutes of Health grants HL75209, HL87012, and HL80711, and WCU Program (R31-2008-000-10010-0) (HJ), as well as an American Heart Association pre-doctoral fellowship 0715417B (RFA).

Imaging studies were performed in part through the use of the Emory Internal Medicine Imaging Core, (supported by NIH grants PO1 HL05800 and PO1 HL075209).


  • Science & Technology
  • Multidisciplinary Sciences
  • FLOW
  • Cardiology
  • Endothelium
  • Calcification
  • BMP signaling
  • Alizarin staining
  • Phosphorylation
  • Cardiac transplantation
  • Immunohistochemistry techniques
  • Surgical and invasive medical procedures

Preferential Activation of SMAD1/5/8 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6


Journal Title:



Volume 6, Number 6


, Pages e20969-e20969

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2011 Ankeny et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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