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This article is part of the supplement: 18th Scientific Symposium of the Austrian Pharmacological Society (APHAR)

Open Access Meeting abstract

Tolerance to nitroglycerin through proteasomal degradation of aldehyde dehydrogenase-2 in a genetic mouse model of ascorbate deficiency

Astrid Schrammel1*, Gerald Wölkart1, Matteo Beretta1, Heike Stessel1, Kurt Schmidt1, Nobuyo Maeda2 and Bernd Mayer1

Author Affiliations

1 Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria

2 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA

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BMC Pharmacology and Toxicology 2012, 13(Suppl 1):A36  doi:10.1186/2050-6511-13-S1-A36

The electronic version of this article is the complete one and can be found online at:

Published:17 September 2012

© 2012 Schrammel et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


L-Gulonolactone oxidase-deficient mice (Gulo(−/−)) were used to study the effects of ascorbate deficiency on aortic relaxation and lowering of blood pressure by nitroglycerin (GTN). Special emphasis was given to changes in expression and activity of vascular aldehyde dehydrogenase-2 (ALDH2), which has been recently characterized as key enzyme of vascular GTN bioactivation.


Ascorbate deficiency was induced in Gulo(−/−) mice by ascorbate deprivation for 4 weeks. Some of the animals were concomitantly treated with the proteasome inhibitor bortezomib and effects were compared with ascorbate-supplemented Gulo(−/−), untreated or nitrate-tolerant wild-type mice. Aortic relaxation of the experimental groups to GTN, acetylcholine and the NO donor diethylamine NONOate was studied. Changes in mRNA and protein expression of vascular ALDH2 were quantified by real-time PCR and immunoblotting, respectively, and aortic GTN denitration rates were determined by thin layer chromatography. Ubiquitination of proteins was analyzed by immunoblotting.


Like GTN treatment, ascorbate deprivation induced vascular tolerance to GTN that was associated with markedly decreased rates of GTN denitration. Ascorbate deficiency did not affect ALDH2 mRNA levels, but reduced ALDH2 protein expression and the total amount of ubiquitinated proteins to about 40% of wild-type controls. These effects were largely prevented by ascorbate supplementation or treating Gulo(−/−) mice with the 26S proteasome inhibitor bortezomib.


Our data indicate that ascorbate deficiency results in vascular tolerance to GTN via proteasomal degradation of ALDH2. The results support the view that impaired ALDH2-catalyzed metabolism of GTN contributes significantly to the development of vascular nitrate tolerance and reveal a hitherto unrecognized protective effect of ascorbate in the vasculature.


This work was supported by the FWF Austrian Science Fund (grant P21693).