α-Tocopherol Amplifies Phosphorylation of Endothelial Nitric Oxide Synthase at Serine 1177 and its Short-Chain Derivative Trolox Stabilizes Tetrahydrobiopterin

Heller, Regine; Hecker, M.; Stahmann, Nadine; Thiele, Jens J.; Werner-Felmayer, Gabriele; Werner, Ernst R.

doi:10.1016/j.freeradbiomed.2004.05.017

Cited by 22 publications

(14 citation statements)

References 38 publications

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“…The results presented here agree with a previous report showing that α‐tocopherol as well as γ‐ and δ‐tocopherol enhanced NO production and modified eNOS phosphorylation in platelets, although the residue serine 1177 was not investigated 51. In contrast, phorbol ester‐mediated overall eNOS phosphorylation in platelets was inhibited by α‐tocopherol,50 suggesting that PKC‐mediated phosphorylation of the eNOS residue threonine 495 was reduced, which was, however, not confirmed in our experiments 56…”

Section: Resultssupporting

confidence: 68%

“…Data were calculated from the difference between stimulated and unstimulated cells (mean ± SEM; n = 4; * P < 0.05 vs. untreated controls; + p < 0.05 vs. cells pretreated with ascorbic acid alone). (From Heller et al 56 Reprinted by permission.)…”

Section: Resultsmentioning

confidence: 99%

“…These data are in line with an in vivo study in mice where vitamin E did not affect the metabolism of tetrahydrobiopterin54 and indicate that a hydrophilic structure of antioxidants may be required to interfere with oxidative degradation of tetrahydrobiopterin. Interestingly, trolox, a water‐soluble derivative of α‐tocopherol that is lacking the phytyl side‐chain, was able to increase intracellular tetrahydrobiopterin levels and to potentiate endothelial NO formation 56…”

Section: Resultsmentioning

confidence: 99%

“…( B ) Densitometric analysis (values are normalized to the staining of the untreated control) (mean ± SEM; n = 5; * P < 0.05 vs. untreated controls). (From Heller et al 56 Reprinted by permission.)…”

Section: Resultsmentioning

confidence: 99%

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α‐Tocopherol and Endothelial Nitric Oxide Synthesis

Heller

Werner-Felmayer

Werner

2004

Annals of the New York Academy of Sciences

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Nitric oxide (NO), a central regulator of vascular tone and homeostasis, is generated upon activation of endothelial NO synthase (eNOS), which is mediated by an increase of intracellular calcium and/or by eNOS phosphorylation. A reduction of NO bioavailability leads to endothelial dysfunction that has been shown to be improved by alpha-tocopherol in certain conditions. The underlying mechanisms, however, are not completely clarified. The present study was performed to investigate whether alpha-tocopherol is able to affect endothelial NO synthesis. The formation of NO was measured in human umbilical vein endothelial cells using citrulline (coproduct) and cGMP (product of the NO-activated soluble guanylate cyclase) as indicator molecules. alpha-Tocopherol (10-200 microM, 24 hr) increased ionomycin-induced citrulline and cGMP formation in intact cells in a concentration-dependent manner. In parallel, ionomycin-stimulated phosphorylation of eNOS at serine 1177, known to support enzyme activation, was increased by alpha-tocopherol, suggesting that this was the mechanism responsible for enhanced NO formation. The effect of alpha-tocopherol was dependent on its hydrophobic structure because it was mimicked by gamma-tocopherol but not by trolox, a hydrophilic derivative of alpha-tocopherol. Coincubation with ascorbic acid (100 microM, 24 hr) amplified the effects of alpha-tocopherol on eNOS phosphorylation and NO formation, which is possibly related to the regeneration of oxidized alpha-tocopherol by ascorbate. Our data suggest that vasoprotective effects of alpha-tocopherol in vivo may be related to an increase of NO formation. The effect of alpha-tocopherol seems to be dependent on tissue saturation with ascorbic acid, and both vitamins may act synergistically to provide optimal conditions for endothelial NO formation.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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α‐Tocopherol and Endothelial Nitric Oxide Synthesis

Heller

Werner-Felmayer

Werner

2004

Annals of the New York Academy of Sciences

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“…Although this effect is accompanied by a decrease in cyclo-oxygenase (COX) 1 and 2 activity, the net effect is an increase in the production of vasodilating prostanoids PGE 2 and PGI 2 [17]. Additionally, vitamin E was shown to enhance the phosphorylation of endothelial nitric oxide synthase (eNOS) on serine 1177, resulting in an amplification of its action [18,19]. These results translate to increased levels of NO metabolites following vitamin E treatment [20].…”

Section: Vitamin Ementioning

confidence: 99%

Antioxidant Vitamins and Their Use in Preventing Cardiovascular Disease

2010

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Atherosclerosis remains one of the leading causes of death in Western populations. Subsequent to the discovery that oxidative stress plays a pivotal role in the development and progression of atherosclerosis, vitamins C and E, along with other antioxidants, were studied as potential therapies for the disease. However, while in vitro and in vivo studies showed promising antiatherogenic effects for vitamins C and E, clinical trials in which patients were given high doses of vitamin E or C showed no benefit and even possible harm. This review will attempt to summarize the known mechanistic data regarding the biochemical effects of vitamins C and E and their relevance to atherosclerosis, and offer an explanation for the failure of clinical trials to show that supplementation with these vitamins provides any benefit when given indiscriminately. We provide one example of how pharmacogenomics may be used to identify a sub-population which may indeed benefit from antioxidant supplementation.

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