Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase

Axton, Elizabeth R.; Cristobal, Eleonso; Choi, Jaewoo; Miranda, Cristobal L.; Stevens, Jan F.

doi:10.3389/fphar.2018.01085

Cited by 13 publications

(13 citation statements)

References 53 publications

(65 reference statements)

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“…Topical NTG can induce venous and arterial vessel dilation by smooth muscle relaxation of their walls 14 . Although NTG is bioactivated into NO, there are some suggestions that its vasodilator effect is due to a NO-independent mechanism, which is evidenced in recent experimental and clinical studies showing that NO alone cannot exert all of the vasodilatory effects, in turn suggesting that additional vasoactive mechanisms are involved 48,49 . NTG also can exert its vasodilatory action through the activation of endothelial cells to synthesize prostacyclin.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Sildenafil and/or Nitroglycerin on Random-pattern Skin Flaps After Nicotine Application in Rats

Ellabban

Fattah

Kader

et al. 2020

Sci Rep

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Smoking aggravates skin necrosis as a complication of random-pattern flap ischaemia. Sildenafil and nitroglycerin (NTG) are vasodilator agents that may affect skin flap survival. Fifty rats were subjected to a dorsal random-pattern flap operation and randomly divided into 5 groups. The control group received no treatment. The ischaemic group were administered local nicotine injections. The sildenafil group were administered oral sildenafil treatment in addition to the same intervention as the ischaemic group. The NTG group received topical NTG ointment application instead of sildenafil. The combined group were given both sildenafil and NTG treatments. After 7 days, all rats were sacrificed for flap assessment. Flap survival percentages at the 3 rd and 7 th days were significantly higher in the combined group than in the other study groups. Histologically, the ischaemic group exhibited dermal disorganization and inflammatory cell infiltration, which were improved in the 3 treated groups; however, the combined group presented the most relevant effect. The epidermal thickness showed a decrease in the ischaemic group (23.1 μm) that was significantly increased in the sildenafil (28.4 μm), NTG (28.8 μm) and combined (35.8 μm) groups. Immunohistochemically, the combined group exhibited a significant decrease in the apoptotic index and an increase in the proliferative index (2.3 and 56.9%, respectively) compared to those in the ischaemic (63.2 and 3%), sildenafil (41.7 and 28.1%) and NTG (39.3 and 30.4%) groups. Transmission electron microscopy (TEM) showed that the combined group displayed improvement in most of the ischaemic changes. Our analyses suggest that the combined use of sildenafil and NTG is more efficacious than using only one of these treatments for skin flap survival.Random skin flaps are widely used options for the reconstruction of large acquired or congenital skin defects 1 . Survival of these flaps is highly reliant on oxygen delivery to their tissues 2 . The main challenge is that the distal parts of the flap suffer from a reduced blood supply, which can trigger skin necrosis 3 . This reduction in the blood supply is mainly caused by anatomical or haemodynamic factors 4 . During vascular regeneration, ischaemia/reperfusion injury occurs, promoting oxidative stress and apoptosis 3 . Additionally, other factors, such as inadequate angiogenesis and inflammatory reactions, play roles in the pathogenesis of flap necrosis 5 .Skin flap ischaemic necrosis and increased incidence of infection can be aggravated by nicotine, which endangers the results of plastic skin reconstruction 6 . Smoking increases the risk of skin flap complications, which has been observed in clinical and experimental studies in both rats and hamsters 7 . Smokers have a higher risk of developing skin flap necrosis, namely, 13 times higher than that of non-smokers, which can result in flap loss or secondary contractures that negatively affect the aesthetic outcomes 6,8 . The potential mechanisms of this increased risk in smokers are highly...

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Section: Discussionmentioning

confidence: 99%

The Effects of Sildenafil and/or Nitroglycerin on Random-pattern Skin Flaps After Nicotine Application in Rats

Ellabban

Fattah

Kader

et al. 2020

Sci Rep

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“…Samples were spun for 10 min at 14,000× g at 4 • C and the supernatant was transferred to mass spectrometry vials (Microsolv, Leland, NC, USA). LC-MS/MS was carried out with a method previously described [6,7,15] with some differences. Briefly, data-dependent acquisition (DDA) in both the positive and the negative ion mode was conducted using a Shimadzu Nexera UPLC system connected to an AB SCIEX TripleTOF ® 5600 mass spectrometer (AB SCIEX, Concord, Canada).…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

“…From metabolomics analyses of zebrafish fed a diet lacking sufficient AA, we established that AA deficiency, which causes oxidative stress, activates the purine nucleotide cycle to regenerate ATP [6]. Recently, we reported that AA prevents cellular 2 of 13 nitrate tolerance in glyceryl trinitate-treated porcine renal epithelial cells, which is relevant to angina [7]. Using a mass spectrometry-based metabolomics approach, we found that AA protects xanthine oxidase from glyceryl trinitrate-induced inactivation, which is relevant because this enzyme plays a role in the conversion of glyceryl trinitrate into the vasoactive metabolite, nitric oxide [7].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we reported that AA prevents cellular 2 of 13 nitrate tolerance in glyceryl trinitate-treated porcine renal epithelial cells, which is relevant to angina [7]. Using a mass spectrometry-based metabolomics approach, we found that AA protects xanthine oxidase from glyceryl trinitrate-induced inactivation, which is relevant because this enzyme plays a role in the conversion of glyceryl trinitrate into the vasoactive metabolite, nitric oxide [7]. These examples illustrate how a data-driven metabolomics approach can reveal novel functions of AA.…”

Section: Introductionmentioning

confidence: 99%

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Vitamin C Activates the Folate-Mediated One-Carbon Cycle in C2C12 Myoblasts

et al. 2020

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Vitamin C (L-ascorbic acid, AA) is an essential cellular antioxidant and cofactor for several α-ketoglutarate-dependent dioxygenases. As an antioxidant, AA interacts with vitamin E to control oxidative stress. While several reports suggest an interaction of AA with folate (vitamin B9) in animals and humans, little is known about the nature of the interaction and the underlying molecular mechanisms at the cellular level. We used an untargeted metabolomics approach to study the impact of AA on the metabolome of C2C12 myoblast cells. Compared to untreated cells, treatment of C2C12 cells with AA at 100 µM resulted in enhanced concentrations of folic acid (2.5-fold) and 5-methyl-tetrahydrofolate (5-methyl-THF, 10-fold increase) whereas the relative concentrations of 10-formyl-tetrahydrofolate decreased by >90% upon AA pretreatment, indicative of increased utilization for the biosynthesis of active THF metabolites. The impact of AA on the folate-mediated one-carbon cycle further manifested itself as an increase in the levels of methionine, whose formation from homocysteine is 5-methyl-THF dependent, and an increase in thymidine, whose formation from deoxyuridine monophosphate (dUMP) is dependent on 5,10-methylene-THF. These findings shed new light on the interaction of AA with the folate-mediated one-carbon cycle and partially explain clinical findings that AA supplementation enhances erythrocyte folate status and that it may decrease serum levels of homocysteine, which is considered as a biomarker of cardiovascular disease risk.

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“…ALDH1, was also capable of reducing GTN to biologically active NO (Tsou et al, 2011). Axton and others (Axton et al, 2018) indicated that xanthine oxidase (XO; EC 1.17.3.2) was a critical enzyme for metabolic bio-activation of GTN to NO.…”

Section: Introductionmentioning

confidence: 99%

Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase activity? A contribution to the ongoing discussion

et al. 2019

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The aim of the study presented here was an attempt to answer the question posed in the title: Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase (ALDH) activity? Here, we investigated the effect of administration (separately or jointly) of lipoic acid (LA), nitroglycerin (GTN), and disulfiram (DSF; an irreversible in vivo inhibitor of all ALDH isozymes (including ALDH2)), on the development of tolerance to GTN. We also assessed the total activity of ALDH in the rat liver homogenates. Our data revealed that not only DSF and GTN inhibited the total ALDH activity in the rat liver, but LA also proved to be an inhibitor of this enzyme. At the same time, the obtained results demonstrated that the GTN tolerance did not develop in GTN, DSF and LA jointly treated rats, but did develop in GTN and DSF jointly treated rats. This means that the ability of LA to prevent GTN tolerance is not associated with the total ALDH activity in the rat liver. In this context, the fact that animals jointly receiving GTN and DSF developed tolerance to GTN, and in animals that in addition to GTN and DSF also received LA such tolerance did not develop, is – in our opinion – a sufficient premise to conclude that the nitrate tolerance certainly is not caused by a decrease in the activity of any of the ALDH isoenzymes present in the rat liver, including ALDH2. However, many questions still await an answer, including the basic one: What is the mechanism of tolerance to nitroglycerin?

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Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase

Cited by 13 publications

References 53 publications

The Effects of Sildenafil and/or Nitroglycerin on Random-pattern Skin Flaps After Nicotine Application in Rats

The Effects of Sildenafil and/or Nitroglycerin on Random-pattern Skin Flaps After Nicotine Application in Rats

Vitamin C Activates the Folate-Mediated One-Carbon Cycle in C2C12 Myoblasts

Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase activity? A contribution to the ongoing discussion

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