Inhibition of protein kinase C activity and vascular smooth muscle cell growth by d-α-tocopherol

Boscoboinik, Daniel; Chatelain, Eric; Bartoli, Gianna-M.; Stäuble, Barbara; Azzi, Angelo

doi:10.1016/0167-4889(94)90277-1

Cited by 27 publications

(14 citation statements)

References 32 publications

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“…At 25-50 M, ␣-tocopherol is known to regulate signal transduction pathways by mechanisms that are independent of its antioxidant properties (9,10). This study provides the first evidence describing a signal transduction regulatory role of tocotrienol.…”

Section: Discussionmentioning

confidence: 64%

“…At concentrations 25-50 M, ␣-tocopherol is known to regulate signal transduction pathways by mechanisms that are independent of its antioxidant properties. ␣-Tocopherol, but not ␤-tocopherol having comparable antioxidant properties, inhibited inducible protein kinase C activity in smooth muscle cells (9,10). The signal transduction regulatory properties of tocotrienols, however, are yet unknown.…”

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confidence: 99%

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Molecular Basis of Vitamin E Action

Sen

Khanna

Roy

et al. 2000

Journal of Biological Chemistry

279

113

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HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than ␣-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of ␣-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60 c-Src kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of ␣-tocotrienol, but not ␣-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active cSrc sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. ␣-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4 -10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.

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Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

Molecular Basis of Vitamin E Action

Sen

Khanna

Roy

et al. 2000

Journal of Biological Chemistry

279

113

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“…Similarly, these glycated particles, irrespective of the modifying agent or extent of modification, did not give rise to enhanced total cholesterol, total cholesterol ester, or percentage cholesterol ester levels when incubated with HUVECs or A7r5 smooth muscle cells. Serum deprivation of the A7r5 cells, to mimic a purported in vivo state [47,48], also did not affect cellular viability, protein, free cholesterol, and total cholesterol ester levels.…”

Section: Discussionmentioning

confidence: 99%

Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells

2005

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Aims/hypothesis: Previous studies have implicated the glycoxidative modification of low-density lipoprotein (LDL) by glucose and aldehydes (apparently comprising both glycation and oxidation), as a causative factor in the elevated levels of atherosclerosis observed in diabetic patients. Such LDL modification can result in unregulated cellular accumulation of lipids. In previous studies we have characterized the formation of glycated, but nonoxidized, LDL by glucose and aldehydes; in this study we examine whether glycation of LDL, in the absence of oxidation, gives rise to lipid accumulation in arterial wall cell types. Methods: Glycated LDLs were incubated with macrophage, smooth muscle, or endothelial cells. Lipid loading was assessed by HPLC analysis of cholesterol and individual esters. Oxidation was assessed by cholesterol ester loss and 7-ketocholesterol formation. Cell viability was assessed by lactate dehydrogenase release and cell protein levels. Results: Glycation of LDL by glycolaldehyde and methylglyoxal, but not glucose (in either the presence or absence of copper ions), resulted in cholesterol and cholesterol ester accumulation in macrophage cells, but not smooth muscle or endothelial cells. The extent of lipid accumulation depends on the degree of glycation, with increasing aldehyde concentration or incubation time, giving rise to greater extents of particle modification and lipid accumulation. Modification of lysine residues appears to be a key determinant of cellular uptake. Conclusions/interpretation:These results are consistent with LDL glycation, in the absence of oxidation, being sufficient for rapid lipid accumulation by macrophage cells. Aldehyde-mediated "carbonyl-stress" may therefore facilitate the formation of lipid-laden (foam) cells in the artery wall.

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“…Following supplementation to humans, the level of ␣-tocotrienol in the plasma has been estimated to be 1 M (7). At concentrations of 25-50 M, ␣-tocopherol is known to regulate signal transduction pathways by mechanisms that are independent of its antioxidant properties (8,9). Micromolar amounts of tocotrienol, but not tocopherol, have been shown to suppress the activity of hydroxy-3-methylglutaryl-coenzyme A reductase (10,11).…”

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confidence: 99%

Molecular Basis of Vitamin E Action

Khanna

Roy

Ryu

et al. 2003

Journal of Biological Chemistry

261

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Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of ␣-tocotrienol, but not ␣-tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049 -13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar ␣-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and L-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient ␣-tocotrienol. In silico docking studies indicated that ␣-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to ␣-tocotrienol as a potent neuroprotective form of vitamin E.

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Inhibition of protein kinase C activity and vascular smooth muscle cell growth by d-α-tocopherol

Cited by 27 publications

References 32 publications

Molecular Basis of Vitamin E Action

Molecular Basis of Vitamin E Action

Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells

Molecular Basis of Vitamin E Action

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