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-Tocopherol in Smooth Muscle Cells1 ,2
Institute of Biochemistry and Molecular Biology, 3012 Bern, Switzerland
3To whom correspondence should be addressed. E-mail: angelo.azzi{at}mci.unibe.ch.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONInhibition of PKC and...Transcriptional regulation of...{alpha}-Tocopherol-associated...REFERENCES |
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-tocopherol, are not retained by humans. This suggests that
-tocopherol is recognized uniquely; therefore, it may exert an
exclusive function. -Tocopherol possesses distinct properties that
are independent of its prooxidant, antioxidant or
radical-scavenging ability. -Tocopherol specifically inhibits
protein kinase C, the growth of certain cells and the transcription of
the CD36 and collagenase genes. Activation events have also been seen
on the protein phosphatase 2A (PP2A) and on the expression
of other genes (-tropomyosin and connective tissue growth factor).
Neither ß-tocopherol nor probucol possessed the same specialty
functions as -tocopherol. Recently, we isolated a new ubiquitous
cytosolic -tocopherol binding protein (TAP). Its motifs suggest that
it is a member of the hydrophobic ligand-binding protein family
(CRAL-TRIO). TAP may also be involved in the regulation of cellular
-tocopherol concentration and -tocopherol–mediated
signaling.
KEY WORDS: • tocotrienols • tocopherols • cell signaling • -tocopherol binding protein
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONInhibition of PKC and...Transcriptional regulation of...{alpha}-Tocopherol-associated...REFERENCES |
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. Later, in the 1960s,
it was associated with antioxidant function (2)
;
nonoxidant properties were discovered 25 y after that
(3
,4)
. -Tocopherol is the member of the vitamin E group
(-, ß-, 
- and 
-tocopherols and tocotrienols) with the most
biologically significant properties (5
6
7
8
9)
. Unlike others
in the vitamin E group, -tocopherol is found predominantly in
mammalian tissue, rather than in plants (10
11
12
13)
.
When -tocopherol is attacked by fatty acid peroxy radicals, it
becomes, via one-electron oxidation, the -tocopheryl radical; as
a consequence of two-electron oxidation, it becomes
-tocopherylquinone. Under physiologic conditions, the reducing
agents, ascorbic acid and lypoic acid, continuously repair oxidized
-tocopherol, thus preventing a loss of -tocopherol–dependent
cell-signaling events. If the rate of oxidation is greater than the
rate of repair, -tocopherol concentrations in the body will
decrease.
Low levels of -tocopherol have been associated with increased
incidence of coronary artery disease. Conversely, increased intake of
-tocopherol has been shown to have protective effects against heart
disease. Advances have been made in understanding the molecular basis
of atherogenesis, elucidating functions of -tocopherol beyond that
of preventing LDL oxidation. We are on the verge of understanding the
regulatory, nonoxidative response to -tocopherol by crucial cells.
Such responses include inhibition of smooth muscle cell proliferation,
preservation of endothelial function, inhibition of
monocyte-endothelial adhesion, inhibition of monocyte reactive
oxygen species and cytokine release, and inhibition of platelet
adhesion and aggregation.
These cellular responses to -tocopherol are associated with
transcriptional and post-transcriptional events. Activation of
diacylglycerol kinase and protein phosphatase 2A
(PP2A),4
and the inhibition of protein kinase C (PKC), cyclooxygenase,
lipoxygenase and cytokine release by -tocopherol are all examples of
post-transcriptional regulation. -Tocopherol also modulates the
transcriptional regulation of a number of genes, including the liver
collagen I gene, the -tocopherol transfer protein gene, the
-tropomyosin gene and the collagenase (metallo-proteinase 1) gene.
In recent years, several reviews have reported on the action of
-tocopherol at the cellular level (14
15
16
17
18
19
20)
. This brief
report will emphasize the nonantioxidant role of -tocopherol in
cellular modulation.
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Inhibition of PKC and associated cellular functions |
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TOPABSTRACTINTRODUCTIONInhibition of PKC and...Transcriptional regulation of...{alpha}-Tocopherol-associated...REFERENCES |
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-tocopherol was discovered in
1991 to be the cause of the inhibition of vascular smooth muscle cell
proliferation by -tocopherol (3
,4
,21
22
23
24
25)
. Subsequent
reports have confirmed that the inhibition of PKC by -tocopherol
occurs in different cell types such as monocytes, macrophages,
neutrophils, fibroblasts and also mesangial cells
(14
,26
27
28
29
30
31
32
33
34
35
36
37
38)
. -Tocopherol was also found to inhibit
thrombin-induced PKC activation and endothelin secretion in
edothelial cells; ß-tocopherol did not have a similar ability
(39)
. -Tocopherol inhibits phorbol ester–induced shape
changes in erythroleukemia cells (40)
, and also inhibits
PKC-mediated neutrophil-superoxide generation (31)
. In
animal models of atherosclerosis, PKC inhibition by -tocopherol has
also been demonstrated (41
,42)
. -Tocopherol inhibits
PKC activity in a specific manner because ß-tocopherol or Trolox
(43)
does not exert such an effect. -Tocopherol also
produces a significant decrease in monocyte superoxide anion release,
lipid oxidation, and interleukin-1 (IL-1 ß) release and adhesion to
the endothelium. A similar antioxidant, ß-tocopherol, had no effect
on IL-1 ß release (44)
. -Tocopherol inhibits
production of chemokines and inflammatory cytokines in addition to
inhibition of adhesion of monocytes to human aortic endothelial cells
by reducing the expression of adhesion molecules when cells are
activated by inflammatory cytokines (45)
.
The proliferation and inhibition of PKC by a physiologic concentration
of -tocopherol are parallel events in vascular smooth muscle cells
(46
47
48)
. ß-Tocopherol is ineffective in either process
and prevents the inhibitory effect of -tocopherol. Because
-tocopherol and ß-tocopherol have very similar
radical-scavenging abilities, it is clear that the mechanism by
which -tocopherol acts on PKC is not related to these scavenging
properties (49)
. Inhibition by -tocopherol may be seen
only at the cellular level and is not evident with recombinant PKC. The
inhibitory effect of -tocopherol on PKC can be correlated to a
dephosphorylation of PKC. PP2A can be
activated in vitro by treatment with -tocopherol
(50
,51)
. This event may be crucial to the
dephosphorylation of PKC and its subsequent decrease in activity.
-Tocopherol has a PKC-mediated protective effect on human
mesangial cells when exposed to high glucose concentrations
(37)
. Our group observed a similar protective effect
(50
, 51)
. In the studies of King’s group
(37)
, PKC ß-isoform expression was induced by high
glucose. Interestingly, high glucose is concurrently responsible for an
increase in diacylglycerol synthesis. It can be concluded that,
although the mechanism of PKC inhibition by -tocopherol has been
interpreted differently in different laboratories and cellular systems,
considerable agreement exists concerning the inhibition of PKC by
-tocopherol.
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Transcriptional regulation of cellular reactions |
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TOPABSTRACTINTRODUCTIONInhibition of PKC and...Transcriptional regulation of...{alpha}-Tocopherol-associated...REFERENCES |
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-Tocopherol concentration in organisms is dependent upon its
uptake and destruction in radical reactions. Because of this,
modulation of gene expression takes place as -tocopherol
concentrations increase or decrease (52)
. -Tropomyosin
expression is upregulated by -tocopherol, but not by ß-tocopherol,
in rat vascular smooth muscle cells (53)
in a reaction not
mediated by PKC. Age-dependent increase of collagenase (MPP1)
expression can be reduced by -tocopherol (54)
in human
skin fibroblasts.
The liver -tocopherol transfer protein and its mRNA are modulated by
dietary vitamin E deficiencies in rats (55)
, and - and
ß-tocopherol induce expression of hepatic -tocopherol transfer
protein mRNA (56
,57)
. Scavenger receptors are also under
-tocopherol control. -Tocopherol downregulates the activity of
class A scavenger receptors in macrophages (58)
. Another
scavenger receptor gene, CD36, is downregulated at the transcriptional
level by -tocopherol in macrophages and smooth muscles cells.
ß-Tocopherol, however, does not have this regulating ability
(59)
. In conclusion, it appears that -tocopherol is
able to regulate the expression of a number of genes that are
correlated with -tocopherol–associated pathologies. To what extent
these regulatory events are the direct consequence of the interaction
of -tocopherol with a receptor, a transcription factor or an element
of the signal transduction pathways (e.g., PKC or phosphatase) remains
a matter of
investigation.
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-Tocopherol–associated protein (TAP)
|
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TOPABSTRACTINTRODUCTIONInhibition of PKC and...Transcriptional regulation of...{alpha}-Tocopherol-associated...REFERENCES |
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-tocopherol is involved in the regulation of
several genes offers a very challenging opportunity for future studies.
Here, only the existence of a common denominator (an -tocopherol
receptor protein, an -tocopherol sensitive promoter element or an
-tocopherol sensitive transcription factor) has been postulated.
Using molecular cloning into Escherichia coli and in vitro
expression, we recently identified a human (hTAP) and bovine TAP
(60)
. This protein appears to belong to a family of
hydrophobic ligand-binding proteins, which all have the CRAL
(cis-retinal binding motif) sequence in common. By using a
biotinylated -tocopherol derivative and the IASys resonant mirror
biosensor, the purified recombinant protein was shown to bind
tocopherol at a specific binding site with a
Kd of 4.6 x 10-7 mol/L. Northern
analysis shows that hTAP mRNA has a size of 
2.8k bp and is expressed
ubiquitously. The highest amounts of hTAP message are found in the
liver, brain and prostate. In conclusion, hTAP has significant sequence
homology with proteins containing the CRAL-TRIO structural motif
(RALBP, CRALBP, -TTP, SEC 14, PTN 9, RSEC 45). TAP binds
specifically to -tocopherol and biotinylated tocopherol, suggesting
the existence of a hydrophobic pocket possibly analogous to that of
SEC14. The newly discovered TAP is coded for in the human genome by three genes having slightly different 3'-sequences. The real function of these three genes products cannot be predicted precisely, but the very existence of three copies and their ubiquitous distribution point towards an important cellular role. Unbiased hypotheses may consider TAP a cellular binding or interorganelle transport protein, although the possibility of the identification of TAP with a cell receptor, a coreceptor or a transcription factor modulator cannot be underestimated. Coprecipitation experiments and two hybrid studies in progress in our laboratory may give indications, by nearest-neighbor protein interactions, concerning the function of these new cellular tocopherol binding proteins.
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FOOTNOTES |
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2 Supported by the Swiss National Science Foundation, by F. Hoffmann-La-Roche, AG and by the Stiftung für Ernährungsforschung in der Schweiz.
4 Abbreviations: IL, interleukin; PKC, protein kinase C; PP2A, protein phosphatase 2A; TAP, tocopherol-associated protein.
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REFERENCES |
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