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J. Biol. Chem., Vol. 277, Issue 23, 20927-20933, June 7, 2002
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From the Laboratory of Physiologic Studies, National Institute on
Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892
Moderate but not heavy drinking has been
found to have a protective effect against cardiovascular morbidity. We
investigated the effects of ethanol (EtOH) treatment on the cell
survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt pathway in
cultured human umbilical vein endothelial cells (HUVEC). Exposure of
cells to 2-20 mM EtOH resulted in rapid (<10 min)
induction of Akt phosphorylation that could be prevented by pertussis
toxin or the PI3K inhibitors wortmannin and LY294002. Among the
downstream effectors of PI3K/Akt, p70S6 kinase, glycogen synthase
kinase 3
Dose-dependent Activation of Antiapoptotic
and Proapoptotic Pathways by Ethanol Treatment in Human Vascular
Endothelial Cells
DIFFERENTIAL INVOLVEMENT OF ADENOSINE*
,
/
, and I
B- were phosphorylated, the latter
resulting in 3-fold activation of NF-B. EtOH also activated p44/42
mitogen-activated protein kinase in a PI3K-dependent manner. Low concentrations of EtOH increased endothelial nitric-oxide synthase activity, which could be blocked by transfection of
HUVEC with dominant-negative Akt, implicating the PI3K/Akt pathway in this effect. The adenosine A1 receptor antagonist
1,3-dipopylcyclopentylxanthine prevented the phosphorylation of Akt
observed in the presence of EtOH, adenosine, or the A1 agonist
N6-cyclopentyladenosine. Incubation of HUVEC
with 50-100 mM EtOH resulted in mitochondrial permeability
transition and caspase-3 activation followed by apoptosis, as
documented by DNA fragmentation and TUNEL assays. EtOH-induced
apoptosis was unaffected by DPCPX and was potentiated by wortmannin or
LY294002. We conclude that treatment with low concentrations of EtOH
activates the cell survival promoting PI3K/Akt pathway in endothelial
cells by an adenosine receptor-dependent mechanism and
activation of the proapoptotic caspase pathway by higher concentrations
of EtOH via an adenosine-independent mechanism can mask or counteract
such effects.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
On leave from the Institute of Immunology, University of Science
and Technology of China, Hefei 230027, China.
§
To whom correspondence should be addressed: National Institute on
Alcohol Abuse and Alcoholism, National Institutes of Health, 12420 Parklawn Dr., Rm. 120, MSC-8115, Bethesda, MD 20892-8115. Tel.:
301-443-2069; Fax: 301-480-0257; E-mail: gkunos@mail.nih.gov.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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