Upregulation of glucose metabolism during intimal lesion formation is coupled to the inhibition of vascular smooth muscle cell apoptosis: Role of GSK3β

Academic Article


  • The purpose of this study was to define the role of metabolic regulatory genes in the pathogenesis of vascular lesions. The glucose transporter isoform, GLUT1, was significantly increased in the neointima after balloon injury. To define the role of GLUT1 in vascular biology, we established cultured vascular smooth muscle cells (VSMCs) with constitutive upregulation of GLUT1, which led to a threefold increase in glucose uptake as well as significant increases in both nonoxidative and oxidative glucose metabolism as assessed by 13C-nuclear magnetic resonance spectroscopy. We hypothesized that the differential enhancement of glucose metabolism in the neointima contributed to formation of lesions by increasing the resistance of VSMCs to apoptosis. Indeed, upregulation of GLUT1 significantly inhibited apoptosis induced by serum withdrawal (control 20 ± 1% vs. GLUT1 11 ± 1%, P < 0.0005) as well as Fas-ligand (control 12 ± 1% vs. GLUT1 6 ± 1.0%, P < 0.0005). Provocatively, the enhanced glucose metabolism in GLUT1 overexpressing VSMC as well as neointimal tissue correlated with the inactivation of the proapoptotic kinase, glycogen synthase kinase 3β (GSK3β). Transient overexpression of GSK3β was sufficient to induce apoptosis (control 7 ± 1% vs. GSK3β 28 ± 2%, P < 0.0001). GSK3β-induced apoptosis was significantly attenuated by GLUT1 overexpression (GSK3β 29 ± 3% vs. GLUT1 + GSK3β 6 ± 1%, n = 12, P < 0.001), suggesting that the antiapoptotic effect of enhanced glucose metabolism is linked to the inactivation of GSK3β. Taken together, upregulation of glucose metabolism during intimal lesion formation promotes an antiapoptotic signaling pathway that is linked to the inactivation of GSK3β.
  • Published In

  • Diabetes  Journal
  • Digital Object Identifier (doi)

    Author List

  • Hall JL; Chatham JC; Eldar-Finkelman H; Gibbons GH
  • Start Page

  • 1171
  • End Page

  • 1179
  • Volume

  • 50
  • Issue

  • 5