Studies of renal injury. II. Activation of the glucose transporter 1 (GLUT1) gene and glycolysis in LLC-PK1 cells under Ca2+ stress.

Dominguez, Jesus H.; Song, Buguang; Liu-Chen, Shuxian; Qulali, Mona; Howard, Randy L.; Lee, Chao‐Hung; McAteer, James A.

doi:10.1172/jci118805

Cited by 21 publications

(25 citation statements)

References 55 publications

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“…Indeed, this study demonstrates that the upregulation of glucose transport significantly inhibits the percentage of VSMCs undergoing apoptosis in response to both serum with- drawal and Fas-ligand. Our findings support previous work from our laboratory and others in VSMCs, proximal tubule-like cells, and the myocardium, demonstrating that glucose metabolism is of critical importance for cell survival (10,(41)(42)(43).…”

Section: Discussionsupporting

confidence: 91%

Upregulation of Glucose Metabolism During Intimal Lesion Formation Is Coupled to the Inhibition of Vascular Smooth Muscle Cell Apoptosis

et al. 2001

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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 13 C-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 3␤ (GSK3␤). Transient overexpression of GSK3␤ was sufficient to induce apoptosis (control 7 ؎ 1% vs. GSK3␤ 28 ؎ 2%, P < 0.0001). GSK3␤-induced apoptosis was significantly attenuated by GLUT1 overexpression (GSK3␤ 29 ؎ 3% vs. GLUT1 ؉ GSK3␤ 6 ؎ 1%, n ‫؍‬ 12, P < 0.001), suggesting that the antiapoptotic effect of enhanced glucose metabolism is linked to the inactivation of GSK3␤. Taken together, upregulation of glucose metabolism during intimal lesion formation promotes an antiapoptotic signaling pathway that is linked to the inactivation of GSK3␤. Diabetes 50:1171-1179, 2001T he risk of restenosis and atherosclerosis after balloon angioplasty is significantly elevated in individuals with diabetes (1-3). This suggests a potential link between vascular smooth muscle cell (VSMC) glucose metabolism and the progression of lesion formation. However, the contributing role of glucose metabolism to the process of vascular lesion formation in the nondiabetic population has not been defined. Recent in vivo studies from our laboratory and others indicate that intimal VSMCs seem to have an intrinsic resistance to apoptosis (4 -6). We hypothesized that a component of the intrinsic property of intimal VSMCs to survive was related to a significant alteration in metabolic regulatory pathways.VSMCs exhibit unusually high rates of glucose utilization and lactate production under normal, well-oxygenated conditions (7,8). Glucose metabolism seems to be an important determinant of vascular reactivity (9). Moreover, recent work from our laboratory has demonstrated that hyperglycemia inhibits medial VSMC apoptosis in the murine carotid artery in response to a reduction in blood flow (10). Thus, we postulated that adaptive alterations in glucose regulatory pathways and metabolism contributed to the antiapoptotic phenotype of neointimal VSMCs.Glucose transport is the rate-limiting step in glucose metabo...

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Section: Discussionsupporting

confidence: 91%

Upregulation of Glucose Metabolism During Intimal Lesion Formation Is Coupled to the Inhibition of Vascular Smooth Muscle Cell Apoptosis

et al. 2001

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“…Neuronal metabolic needs depend on the electric activity of the neurons, and glutamate released by neuronal electric activity is known to induce astrocytic Ca 2ϩ waves (Dani et al, 1992). Furthermore, the GLUT-1 glucose transporter present in endothelial cells, and also in astrocytes (Vannucci et al, 1997), has been reported to increase its expression in response to an increase in [Ca 2ϩ ] i (Mitani et al, 1995(Mitani et al, , 1996Dominguez et al, 1996). Astrocyte-endothelial Ca 2ϩ signals triggered by neuronal activity could thus act by stimulating glucose uptake from the microcirculation.…”

Section: Discussionmentioning

confidence: 99%

Inositol-trisphosphate-dependent intercellular calcium signaling in and between astrocytes and endothelial cells

Leybaert

Paemeleire

Strahonja

et al. 1998

Glia

130

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“…If calcium plays a role in this response, then buffering calcium should prevent dephosphorylation of histone H3-Ser10 by A23187. Several studies have shown that BAPTA-AM and EGTA selectively chelate intracellular and extracellular calcium, respectively (Dominguez et al, 1996;Maloney et al, 1999;Gantt et al, 2000). Thus, cells were pretreated with 50 mM BAPTA-AM for 2 h prior to the addition of A23187 in medium containing 3 mM EGTA.…”

Section: Effects Of A23187 or Thapisgargin On Global Histone H3-ser10mentioning

confidence: 99%

Increases in intracellular calcium dephosphorylate histone H3 at serine 10 in human hepatoma cells: Potential role of protein phosphatase 2A–protein kinase CβII complex

Huang

Batra

Atkins

et al. 2005

Journal Cellular Physiology

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We present evidence that increases in intracellular calcium, induced by treatment with calcium ionophore A23187 or the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin, dephosphorylated histone H3 at serine10 (histone H3-Ser10) in a dose-dependent manner in human hepatoma HepG2 cells. Inhibition of p42/44MAPK, pp90RSK, or p38MAPK did not affect the ability of A23187 to dephosphorylate histone H3-Ser10. This response is significantly blocked by okadaic acid, indicating a requirement for protein phosphatase 2A (PP2A). A23187 increased the activity of PP2A towards phosphorylated histone H3-Ser10. Furthermore, pretreatment with calphostin C, a selective protein kinase C (PKC) inhibitor, blocked A23187-dependent dephosphorylation of histone H3-Ser10, and coimmunoprecipitation analysis showed PP2A association with the PKCbetaII isoform. Unlike untreated cells, coimmunoprecipitated complex from A23187-treated cells showed greater dephosphorylation of histone H3-Ser10 in a PP2A-dependent manner. Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform, thus supporting a role for intracomplex regulation. Finally, chromatin immunoprecipitation assays following exposure to A23187 and okadaic acid revealed regulatory role of histone H3-Ser10 phosphorylation in selective gene induction. Altogether, our findings suggest a novel role for calcium in modulating histone H3-Ser10 phosphorylation level and led us to propose a model emphasizing PP2A activation, occurring downstream following perturbations in calcium homeostasis, as key event in dephosphorylating histone H3-Ser10 in mammalian cells.

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Studies of renal injury. II. Activation of the glucose transporter 1 (GLUT1) gene and glycolysis in LLC-PK1 cells under Ca2+ stress.

Cited by 21 publications

References 55 publications

Upregulation of Glucose Metabolism During Intimal Lesion Formation Is Coupled to the Inhibition of Vascular Smooth Muscle Cell Apoptosis

Upregulation of Glucose Metabolism During Intimal Lesion Formation Is Coupled to the Inhibition of Vascular Smooth Muscle Cell Apoptosis

Inositol-trisphosphate-dependent intercellular calcium signaling in and between astrocytes and endothelial cells

Increases in intracellular calcium dephosphorylate histone H3 at serine 10 in human hepatoma cells: Potential role of protein phosphatase 2A–protein kinase CβII complex

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