Equilibrative nucleoside transporter 1 expression is downregulated by hypoxia in human umbilical vein endothelium
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Date
2005
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Abstract
Reduced oxygen level (hypoxia) induces endothelial dysfunction and release of the endogenous nucleosideadenosine. Human umbilical vein endothelium (HUVEC) function in an environment with 3% to 5% O2and exhibitefficient adenosine membrane transport via human equilibrative nucleoside transporters 1 (hENT1). We studied whetheradenosine transport and hENT1 expression are altered by hypoxia in HUVEC. Hypoxia (0 to 24 hours, 2% and 1% O2)reduced maximal hENT1-adenosine transport velocity (Vmax) and maximal nitrobenzylthionosine (NBMPR, a high-affinity hENT1 protein ligand) binding, but increased extracellular adenosine concentration. Hypoxia also reducedhENT1 protein and mRNA levels, effects unaltered byN_x0001_-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase[NOS] inhibitor) or PD-98059 (inhibitor of mitogen-activated protein kinase kinase 1 and 2 [MEK1/2]). Hypoxiareduced endothelial NOS (eNOS) activity and eNOS phosphorylation at Ser1177, but increased eNOS protein level.Hypoxia increased (1 to 3 hours), but reduced (24 hours) p42/44mapkphosphorylation. Thus, hypoxia-increasedextracellular adenosine may result from reduced hENT1-adenosine transport in HUVEC. Hypoxia effect seems not toinvolve NO, but p42/44mapkmay be required for the relatively rapid effect (1 to 3 hours) of hypoxia. These results couldbe important in diseases where the fetus is exposed to intrauterine environments poor in oxygen, such as intrauterinegrowth restriction, or where adenosine transport is altered, such as gestational diabetes.
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Endothelium, Hypoxia, Adenosine