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doi:10.1016/j.ejphar.2008.05.051 
Copyright © 2008 Published by Elsevier B.V.
Vitamin D2 supplementation induces the development of aortic stenosis in rabbits: Interactions with endothelial function and thioredoxin-interacting protein
Doan T.M. Ngoa, Irene Stafforda, Darren J. Kellyb, Aaron L. Sverdlova, Ronald D. Wuttkea, Helen Weedonc, Angus K. Nightingalea, Anke C. Rosenkranza, Malcolm D. Smithc, Yuliy Y. Chirkova, Jennifer A. Kennedya and John D. Horowitza, 
, 
Received 15 January 2008;
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Abstract
Understanding of the pathophysiology of aortic valve stenosis (AVS) and finding potentially effective treatments are impeded by the lack of suitable AVS animal models. A previous study demonstrated the development of AVS in rabbits with vitamin D2 and cholesterol supplementation without any hemodynamic changes in the cholesterol supplemented group alone. The current study aimed to determine whether AVS develops in an animal model with vitamin D2 supplementation alone, and to explore pathophysiological mechanisms underlying this process.
The effects of 8 weeks' treatment with vitamin D2 alone (n = 8) at 25,000 IU/4 days weekly on aortic valve structure and function were examined in male New Zealand white rabbits. Echocardiographic aortic valve backscatter (AVBS), transvalvular velocity, and transvalvular pressure gradient were utilized to quantitate changes in valve structure and function. Valvular histology/immunochemistry and function were examined after 8 weeks. Changes in valves were compared with those in endothelial function and in valvular measurement of thioredoxin-interacting protein (TXNIP), a marker/mediator of reactive oxygen species-induced oxidative stress. Vitamin D2 treated rabbits developed AVS with increased AVBS (17.6 ± 1.4 dB vs 6.7 ± 0.8 dB, P < 0.0001), increased transvalvular velocity and transvalvular pressure gradient (both P < 0.01 via 2-way ANOVA) compared to the control group. There was associated valve calcification, lipid deposition and macrophage infiltration. Endothelial function was markedly impaired, and intravalvular TXNIP concentration increased.
In this model, vitamin D2 induces the development of AVS with histological features similar to those of early AVS in humans and associated endothelial dysfunction/redox stress. AVS development may result from the loss of nitric oxide suppression of TXNIP expression.
Keywords: Aortic valve stenosis; Vitamin D; Endothelial function; Thioredoxin-interacting protein; Nitric oxide; Redox stress
Article Outline
- 1. Introduction
- 2. Materials and methods
- 2.1. Experimental protocol
- 2.2. Echocardiographic measurements
- 2.3. Calculation of ultrasound backscatter data analysis
- 2.4. Histology and immunohistochemistry
- 2.5. TXNIP Immunostaining
- 2.6. Endothelial function
- 2.6.1. Plasma ADMA concentrations
- 2.6.2. Isolated aortic preparations
- 2.7. Study analysis/statistics
- 3. Results
- 3.1. Effects of vitamin D2 on aortic valves assessed by echocardiography
- 3.2. Histology and immunohistochemistry
- 3.3. TXNIP immunostaining
- 3.4. Biochemistry
- 3.5. Endothelial function
- 4. Discussion
- Acknowledgements
- References
