GLUT-1 reduces hypoxia-induced apoptosis and JNK pathway activation

Many studies have suggested that enhanced glucose uptake protects cells fro m hypoxic injury. More recently, it has become clear that hypoxia induces a poptosis as well as necrotic cell death. We have previously shown that hypo xia-induced apoptosis can be prevented by glucose uptake and glycolytic met abolism in cardiac myocytes. To test whether increasing the number of gluco se transporters on the plasma membrane of cells could elicit a similar prot ective response, independent of the levels of extracellular glucose, we ove rexpressed the facilitative glucose transporter GLUT-1 in a vascular smooth muscle cell line. After 4 h of hypoxia, the percentage of cells that showe d morphological changes of apoptosis was 30.5 +/- 2.6% in control cells and only 6.0 +/- 1.1 and 3.9 +/- 0.3% in GLUT-1-overexpressing cells. Similar protection against cell death and apoptosis was seen in GLUT-l-overexpressi ng cells treated for 6 h with the electron transport inhibitor rotenone. In addition, hypoxia and rotenone stimulated c-Jun-NH2-terminal kinase (JNK) activity >10-fold in control cell lines, and this activation was markedly r educed in GLUT-l-overexpressing cell lines. A catalytically inactive mutant of MEKK1, an upstream kinase in the JNK pathway, reduced hypoxia-induced a poptosis by 39%. These findings show that GLUT-1 overexpression prevents hy poxia-induced apoptosis possibly via inhibition of stress-activated protein kinase pathway activation.