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

Mollnau, Hanke; Wenzel, Philip; Oelze, Matthias; Treiber, Nicolai; Pautz, Andrea; Schulz, Eberhard; Schuhmacher, Swenja; Reifenberg, Kurt; Stalleicken, Dirk; Scharffetter‐­Kochanek, Karin; Kleinert, Hartmut; Münzel, Thomas; Daiber, Andreas

doi:10.1186/1471-2261-6-44

Cited by 34 publications

(31 citation statements)

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“…Previous studies have shown that vasorelaxation to PETN is attenuated by pharmacological inhibition or gene deletion of ALDH2 Mollnau et al, 2006;Wenzel et al, 2007a). Although these studies provided circumstantial evidence for a role of ALDH2 in vascular bioactivation of PETN, enzymatic metabolism of the tetranitrate has not been demonstrated so far.…”

Section: Discussionmentioning

confidence: 73%

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

et al. 2010

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Mitochondrial aldehyde dehydrogenase (ALDH2) contributes to vascular bioactivation of the antianginal drugs nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN), resulting in cGMP-mediated vasodilation. Although continuous treatment with GTN results in the loss of efficacy that is presumably caused by inactivation of ALDH2, PETN does not induce vascular tolerance. To clarify the mechanisms underlying the distinct pharmacological profiles of GTN and PETN, bioactivation of the nitrates was studied with aortas isolated from ALDH2-deficient and nitrate-tolerant mice, isolated mitochondria, and purified ALDH2. Pharmacological inhibition or gene deletion of ALDH2 attenuated vasodilation to both GTN and PETN to virtually the same degree as long-term treatment with GTN, whereas treatment with PETN did not cause tolerance. Purified ALDH2 catalyzed bioactivation of PETN, assayed as activation of soluble guanylate cyclase (sGC) and formation of nitric oxide (NO). The EC 50 value of PETN for sGC activation was 2.2 Ϯ 0.5 M. Denitration of PETN to pentaerythrityl trinitrate was catalyzed by ALDH2 with a specific activity of 9.6 Ϯ 0.8 nmol ⅐ min Ϫ1 ⅐ mg Ϫ1 and a very low apparent affinity of 94.7 Ϯ 7.4 M. In contrast to GTN, PETN did not cause significant inactivation of ALDH2. Our data suggest that ALDH2 catalyzes bioconversion of PETN in two distinct reactions. Besides the major denitration pathway, which occurs only at high PETN concentrations, a minor high-affinity pathway may reflect vascular bioactivation of the nitrate yielding NO. The very low rate of ALDH2 inactivation, presumably as a result of low affinity of the denitration pathway, may at least partially explain why PETN does not induce vascular tolerance.

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Section: Discussionmentioning

confidence: 73%

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

et al. 2010

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“…PETN protects against endothelial dysfunction and vascular oxidative stress, largely via HO-1-dependent mechanism. [10][11][12][13][14][15] In this study, we provided novel evidence that upregulation of the antioxidant enzyme HO-1 contributed to PETN-mediated cytoprotective effect by inhibiting mitochondrial ROS generation and NOX4 expression. Previous studies have reported that NOX4-dependent O 2…”

Section: Discussionmentioning

confidence: 86%

“…10,11 PETN has been shown to protect against endothelial dysfunction and vascular oxidative stress. [12][13][14][15] Potential effects of PETN treatment in congestive heart failure (CHF) have not been studied yet. Therefore, we investigated the effects of long-term treatment with PETN on progressive cardiac remodeling (dilation and cellular and molecular dysregulations) in CHF rats after extensive myocardial infarction (MI).…”

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confidence: 99%

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

et al. 2015

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Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.

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“…Indeed, it is now accepted that polyphenols could prevent many diseases such as cancers (Yang et al, 2009;Korkina et al, 2009;Khan et al, 2009;Bracke et al, 2008;Franklin and McCubrey, 2007), cardiovascular (Madeira et al, 2009;Jones et al, 2011;Kumar et al, 2008;Agouni et al, 2009;Walter et al, 2008;SchiniKerth et al, 2011;Sall Diallo et al, 2008;Sarr et al, 2006 ; and degenerative diseases (Mollnau et al, 2006;Chen et al, 2007;Berrino, 2002;Meydani, 2002;Meydani, 2001). Encouraging the consumption of fruits and vegetables is now a major public health recommendation.…”

Section: Discussionmentioning

confidence: 99%

“…In the current state of knowledge, oxidative stress is a major cause of this phenomenon (Fadel et al, 2012;Oelze et al, 2010;Daiber et al, 2004;Mollnau et al, 2006). Thus, our hypothesis derives from the antioxidant capacity of compounds to reduce or prevent vascular tolerance to nitrates, by reducing oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

Sarr

Sar²,

Diao³

et al. 2013

J. Clin. Med. Res.

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Treatment failure or tolerance, which rapidly leads to a reduced hemodynamic effects and therapeutic efficacy is the major limitation of long-term use of nitrates, including nitroglycerin (NTG) in the treatment of coronary artery disease. These effects are most often associated with oxidative stress. Thus, in this work, we were interested in the prevention of nitrate tolerance by the antioxidant compounds from Hibiscus sabdariffa L. crude extract, a plant from the Senegalese Pharmacopoeia, rich in polyphenols. Thoracic aorta segments without endothelium were taken from rats and incubated in isolated organ chambers. The vessels were then pre-exposed with the H. sabdariffa polyphenolic extract (HSE, 5.10 -2 g/l) or antioxidants such as N-acetyl cysteine (NAC, 10 -3 M) or vitamin C (VIT C, 10 -2 M), taken as reference. After a 30 min treatment, aortic segments were exposed to NTG (50 μM, 1 h) to induce tolerance state before being contracted to adrenaline (10 -8 to 10 -5 M), and then relaxed with NTG (10 -9 to 10 -5 M). Polyphenols from H. sabdariffa potentiated the relaxant response to NTG, whatever the state of vascular tolerance; the HSE partially corrected the in vitro nitrate tolerance. This work suggests interesting therapeutic perspectives by improving the response to treatment with nitrates in coronary patients.

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

Cited by 34 publications

References 50 publications

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

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