This application is directed towards the study of the role of GLUT1 in the prevention of apoptosis induced by hypoxia in vascular smooth muscle cells. Hypoxia and ischemia have been shown to cause apoptosis in a number of different cell type. The principal investigator has demonstrated that vascular smooth muscle cells undergo apoptosis during hypoxia or after treatment with metabolic inhibitors, the same conditions that stimulate expression of the facilitative glucose transporter, GLUT1. The principal investigator has also demonstrated that over-expression of GLUT 1 prevents hypoxia-induced cell death in these cells by the prevention of apoptosis. Along with the prevention of apoptosis, over-expression of GLUT1 prevented the hypoxia- induced signaling through the stress activated protein kinase cascade but did not affect other mitogen in these cells raising the possibility that the protects effects of GLUT1 was through its effects on stress-activated protein kinase. Over-expression of GLUT1 attenuated the increases intracellular calcium induced by hypoxia. The underlying hypothesis in this application is that GLUT1 over-expression protects vascular smooth muscle cells from apoptosis by reducing activation of the SAPK pathway in conjunction by the reduction of intracellular calcium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060156-02
Application #
2901379
Study Section
Pathology A Study Section (PTHA)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Malhotra, Ricky; Tyson, David W; Rosevear, Henry M et al. (2008) Hypoxia-inducible factor-1alpha is a critical mediator of hypoxia induced apoptosis in cardiac H9c2 and kidney epithelial HK-2 cells. BMC Cardiovasc Disord 8:9
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Nethery, David E; Moore, Bethany B; Minowada, George et al. (2005) Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice. J Appl Physiol 99:298-307
Park, James L; Loberg, Robert D; Duquaine, Damon et al. (2005) GLUT4 facilitative glucose transporter specifically and differentially contributes to agonist-induced vascular reactivity in mouse aorta. Arterioscler Thromb Vasc Biol 25:1596-602
Park, James L; Heilig, Charles W; Brosius 3rd, Frank C (2004) GLUT1-deficient mice exhibit impaired endothelium-dependent vascular relaxation. Eur J Pharmacol 496:213-4
Liu, Jinbo; Nethery, David; Kern, Jeffrey A (2004) Neuregulin-1 induces branching morphogenesis in the developing lung through a P13K signal pathway. Exp Lung Res 30:465-78
Loberg, Robert D; Northcott, Carrie A; Watts, Stephanie W et al. (2003) PI3-kinase-induced hyperreactivity in DOCA-salt hypertension is independent of GSK-3 activity. Hypertension 41:898-902

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