Esterase activity of high-<i>K</i><sub>m</sub> aldehyde dehydrogenase from rat liver mitochondria

Senior, Dave J.; Tsai, Chien-Sheng

doi:10.1139/o90-109

Cited by 6 publications

(4 citation statements)

References 9 publications

(19 reference statements)

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“…These results are in accordance with the observation that the mitochondrial ALDH provides an important bioactivation pathway for GTN [19,20,24,25] and is redox-sensitive [36,37] (see scheme in Figure 4). These facts provide a new link between oxidative stress and impaired GTN bioactivation and accordingly development of tolerance: Mitochondrial ROS oxidatively inactivate the ALDH-2.…”

Section: Discussionsupporting

confidence: 91%

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/-mice

Mollnau

Wenzel

Oelze

et al. 2006

BMC Cardiovasc Disord

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BackgroundChronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance.MethodsTolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 μg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 μg/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria.ResultsChronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD+/- mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS.ConclusionChronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance.

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Section: Discussionsupporting

confidence: 91%

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/-mice

Mollnau

Wenzel

Oelze

et al. 2006

BMC Cardiovasc Disord

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“…This is not contradictory, because ALDH-2 contains three cysteine residues in the catalytic center (Fig. 7), rendering the dehydrogenase activity highly sensitive toward oxidative inactivation (Senior and Tsai, 1990;Tsai and Senior, 1991). In addition to Fig.…”

Section: Discussionmentioning

confidence: 93%

“…5A (right axis) defines the level of total esterase activity in control mitochondria, whereas line 2 defines the oxidation-resistant esterase activity. The esterase activity of ALDH-2 involves redox-sensitive sulfhydryl groups and should be inhibited by oxidants (Senior and Tsai, 1990;Tsai and Senior, 1991). Therefore, this activity is represented by the difference between lines 1 and 2.…”

Section: Downloaded Frommentioning

confidence: 99%

Oxidative Stress and Mitochondrial Aldehyde Dehydrogenase Activity: A Comparison of Pentaerythritol Tetranitrate with Other Organic Nitrates

Daiber¹,

Oelze²,

Coldewey³

et al. 2004

Mol Pharmacol

167

162

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Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN-and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations Ͼ1 M. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.Organic nitrates such as nitroglycerin (glyceryl trinitrate; GTN) are widely used in the therapy of cardiovascular diseases such as stable and unstable angina (Abrams, 1995).The anti-ischemic effects of organic nitrates are largely caused by venous and coronary artery dilation as well as the improvement of collateral blood flow, which all decrease myocardial oxygen consumption. Their use, however, is limited because of the rapid development of tolerance and crosstolerance characterized by decreased sensitivity of the vasculature to the organic nitrates and to endothelium-dependent vasodilators, respectively (Mangione and Glasser,

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“…5). Both activities seem to involve cysteine thiol groups (15,32) and are inhibited by oxidants and thiol-targeted compounds such as Ellman's reagent (8). In 2002, an additional function was attributed to this enzyme when Chen et al (5) identified ALDH-2 as a GTN-bioactivating enzyme.…”

Section: Discussionmentioning

confidence: 99%

Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity

Wenzel

Hink

Oelze

et al. 2007

Journal of Biological Chemistry

148

116

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Chronic therapy with nitroglycerin results in a rapid development of nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 g/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to organic nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves nitrate tolerance.Organic nitrates such as nitroglycerin (glyceryl trinitrate, GTN) 3 have been used for over a century in the therapy of cardiovascular diseases like myocardial infarction, unstable angina, and arterial hypertension (1). However, the usefulness of organic nitrates is limited by tolerance, which develops shortly after onset of treatment. The mechanisms underlying nitrate tolerance remain only in part defined and are most likely multifactorial (2). Previously, we found that 3 days of nitrate treatment doubled vascular superoxide (O 2 . ) production (3), which was also found in human bypass material from GTNtreated patients (4). Chen et al. (5) identified the mitochondrial aldehyde dehydrogenase (ALDH-2) as a GTN-metabolizing enzyme and a possible important component in the processes leading to tolerance. This concept was supported by recent studies in ALDH-2-deficient mice (ALDH-2 Ϫ/Ϫ ) (6). Our laboratory further substantiated this concept in an animal model of in vivo tolerance and extended previous observations by demonstrating that mitochondria are a major source of reactive oxygen species formation in response to acute and chronic GTN challenges (7,8). The importance of the ALDH-2 concept for clinical nitrate tolerance was proven by two in...

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Esterase activity of high-K_m aldehyde dehydrogenase from rat liver mitochondria

Cited by 6 publications

References 9 publications

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/-mice

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/-mice

Oxidative Stress and Mitochondrial Aldehyde Dehydrogenase Activity: A Comparison of Pentaerythritol Tetranitrate with Other Organic Nitrates

Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity

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Esterase activity of high-Km aldehyde dehydrogenase from rat liver mitochondria

Cited by 6 publications

References 9 publications

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/-mice

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/-mice

Oxidative Stress and Mitochondrial Aldehyde Dehydrogenase Activity: A Comparison of Pentaerythritol Tetranitrate with Other Organic Nitrates

Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity

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Esterase activity of high-K_m aldehyde dehydrogenase from rat liver mitochondria