Enhanced glycogen synthase kinase-3β activity mediates hypoxia-induced apoptosis of vascular smooth muscle cells and is prevented by glucose transport and metabolism

Robert D. Loberg, Eileen Vesely, Frank C. Brosius

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

Hypoxia triggers apoptosis in a number of different cell types largely through a mitochondrial cell death pathway, which can be abrogated for the most part by enhanced glucose metabolism. The purpose of the current study was to identify intracellular signaling mechanisms that mediate hypoxia-induced apoptosis and are regulated by glucose metabolism. Hypoxia-induced apoptosis in vascular smooth muscle cells and COS-7 cells was accompanied by a significant reduction in Akt and glycogen synthase kinase-3 (GSK-3) phosphorylation resulting in increased GSK-3 activity. Morphologic features of apoptosis, as well as caspases 3 and 9 activation, were prevented by GSK-3 inhibition with either LiCl or SB216763. Phosphorylation of Akt and GSK-3 was enhanced by glucose metabolism or overexpression of the glucose transporter, GLUT1, and was prevented by glycolytic inhibition. These findings indicate that GSK-3 is an important mediator of hypoxia-induced apoptosis and that GSK-3-mediated apoptotic effects occur via activation of the mitochondrial death pathway. Moreover, the results suggest that prevention of hypoxia-mediated apoptosis by enhanced glucose transport and metabolism results, in part, from inhibition of GSK-3 activation.

Original languageEnglish (US)
Pages (from-to)41667-41673
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number44
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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