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© 2001 by the American Diabetes Association, Inc.
Upregulation of Glucose Metabolism During Intimal Lesion Formation Is Coupled to the Inhibition of Vascular Smooth Muscle Cell Apoptosis
Role of GSK3ß
1 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
2 Department of Radiology, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland
3 Department of Human Genetics, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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 3ß (GSK3ß). Transient overexpression of GSK3ß was sufficient to induce apoptosis (control 7 ± 1% vs. GSK3ß 28 ± 2%, P < 0.0001). GSK3ß-induced apoptosis was significantly attenuated by GLUT1 overexpression (GSK3ß 29 ± 3% vs. GLUT1 + GSK3ß 6 ± 1%, n = 12, P < 0.001), suggesting that the antiapoptotic effect of enhanced glucose metabolism is linked to the inactivation of GSK3ß. Taken together, upregulation of glucose metabolism during intimal lesion formation promotes an antiapoptotic signaling pathway that is linked to the inactivation of GSK3ß.
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