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  • Title: Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.
    Author: Wenzel P, Oelze M, Coldewey M, Hortmann M, Seeling A, Hink U, Mollnau H, Stalleicken D, Weiner H, Lehmann J, Li H, Förstermann U, Münzel T, Daiber A.
    Journal: Arterioscler Thromb Vasc Biol; 2007 Aug; 27(8):1729-35. PubMed ID: 17541025.
    Abstract:
    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 microg/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.
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