Heme oxygenase-1 -: A novel key player in the development of tolerance in response to organic nitrates

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 hemeoxygenase- 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 mu g/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.