Upregulation of glucose metabolism during intimal lesion formation is coupled to the inhibition of vascular smooth muscle cell apoptosis - Role of GSK3 beta

The purpose of this study was to define the role of metabolic regulatory ge nes in the pathogenesis of vascular lesions. The glucose transporter isofor m, 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 GLUT 1, which led to a threefold increase in glucose uptake as well as significa nt increases in both nonoxidative and oxidative glucose metabolism as asses sed by C-13-nuclear magnetic resonance spectroscopy. We hypothesized that t he differential enhancement of glucose metabolism in the neointima contribu ted to formation of lesions by increasing the resistance of VSMCs to apopto sis. Indeed, upregulation of GLUT1 significantly inhibited apoptosis induce d 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). P rovocatively, the enhanced glucose metabolism in GLUT1 overexpressing VSMC as well as neointimal tissue correlated with the inactivation of the proapo ptotic kinase, glycogen synthase kinase 3 beta (GSK3 beta). Transient overe xpression of GSK3 beta was sufficient to induce apoptosis (control 7 +/- 1% vs. GSK3 beta 28 +/- 2%, P < 0.0001). GSK3 beta -induced apoptosis was sig nificantly attenuated by GLUTI overexpression (GSK3 beta 29 +/- 3% vs. GLUT 1 + GSK3 beta 6 +/- 1%, n = 12, P < 0.001), suggesting that the antiapoptot ic effect of enhanced glucose metabolism is linked to the inactivation of G SK3 beta. Taken together, upregulation of glucose metabolism during intimal lesion formation promotes an antiapoptotic signaling pathway that is linke d to the inactivation of GSK3 beta.