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Glucose uptake and adenoviral mediated GLUT1 infection decrease hypoxia-induced HIF-1alpha levels in cardiac
Ricky Malhotra1, David G W Tyson, Hirohito Sone
1Department of Internal Medicine, University of Michigan Medical Center, 1150 W Medical Center Drive, 1560 MSRB II, Ann Arbor, MI 48109-0676, USA. rmalhotr@umich.edu
Journal of Molecular and Cellular Cardiology
|September 18, 2002
Summary
Glucose reduces hypoxia-induced HIF-1alpha in cardiac cells via proteasomal degradation. This novel feedback mechanism may aid cardiac adaptation to low oxygen and ischemia.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- Hypoxia triggers adaptive responses in cardiac myocytes.
- Hypoxia-inducible factor 1-alpha (HIF-1alpha) is upregulated during hypoxia, promoting glucose uptake.
- The role of glucose flux in regulating HIF-1alpha in hypoxic cardiac cells is not fully understood.
Purpose of the Study:
- To investigate the molecular effects of increased glucose on hypoxic cardiac myocytes.
- To elucidate the role of glucose in regulating HIF-1alpha and related pathways.
- To determine the mechanism by which glucose affects HIF-1alpha levels.
Main Methods:
- Primary cultures of neonatal rat cardiac myocytes and H9c2 cells were subjected to hypoxia.
- HIF-1alpha levels were measured with and without glucose, glycolytic inhibitors, or GLUT1 overexpression.
- Ubiquitin-proteasomal pathway activity and HIF-1alpha ubiquitination were assessed.
Main Results:
- Hypoxia upregulated HIF-1alpha, which decreased upon glucose re-addition.
- Glucose uptake and glycolysis reduced HIF-1alpha and p53 levels.
- GLUT1 overexpression reduced HIF-1alpha, apoptosis, and cytochrome c release.
- Inhibition of the ubiquitin-proteasomal pathway prevented glucose-induced HIF-1alpha degradation.
Conclusions:
- Glucose diminishes hypoxia-induced HIF-1alpha protein levels in cardiac myocytes through a ubiquitin-proteasomal pathway.
- GLUT1 overexpression also reduces HIF-1alpha via this mechanism.
- This represents a novel feedback loop for cardiac myocyte adaptation to hypoxia and ischemia.