on May 31, 2007
Published online before print May 31, 2007, doi: 10.1161/ATVBAHA.107.143909
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Submitted on December 11, 2006
Accepted on May 14, 2007
Heme Oxygenase-1. A Novel Key Player in the Development of Tolerance in Response to Organic Nitrates
Philip Wenzel ;
From the II. Medizinische Klinik (P.W., M.O., M.C., U.H., H.M., T.M., A.D.), Johannes-Gutenberg-Universität Mainz, Germany; Institut für Pharmakologie (M.H., H.L., U.F.), Johannes-Gutenberg-Universität Mainz, Germany; Institut für Pharmazie (A.S., J.L.), Friedrich-Schiller-Universität Jena, Germany; Actavis Deutschland GmbH (D.S.), Langenfeld, Germany; and the Department of Biochemistry (H.W.), Purdue University, West Lafayette, Ind.
* To whom correspondence should be addressed. E-mail: tmuenzel{at}uni-mainz.de.
Objective--Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance.
Methods and Results--Wistar rats were treated with PETN or GTN (10.5 or 6.6 µg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography-based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced "tolerance" to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats.
Conclusions--HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest.
Key words: organic nitrates • nitrate tolerance • heme oxygenase-1 • reactive oxygen species
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