Chronic hypoxia resulting in pulmonary hypertension is a major cause of morbidity and mortality in patients with COPD. Currently, long-term oxygen therapy is the only therapy that has been shown to improve survival in these patients. Oxygen therapy is thought to act primarily by preventing the development of pulmonary hypertension in response to chronic arterial hypoxemia. Current models for the development of hypoxia induced pulmonary hypertension propose a cross communication between pulmonary artery smooth muscle cells and endothelial cells. Indeed there is substantial hyperplasia of both cell types during hypoxia resulting in remodeling of the vasculature. At the molecular level, the transcriptional responses to hypoxia are primarily mediated by hypoxia inducible factor (HIF), a heterodimer of HIF- alpha and ARNT subunits. Recently, independent groups of investigators have reported that both HIF-1 alpha and HIF-2 alpha heterozygous mice have markedly reduced pulmonary hypertension in response to arterial hypoxemia. These results support an important role for both of these transcription factors in the development of hypoxia induced pulmonary hypertension. How cells sense oxygen to stimulate HIF activation remains unresolved. In the current grant we will test whether hypoxia stimulates the generation of mitochondrial ROS, which subsequently activate Rho and p38 MAPK signaling pathways to stabilize either HIF-1 or HIF-2 in pulmonary artery smooth muscle cells and endothelial cells. We will also examine the individual consequences of loss of function of HIF-1 alpha or HIF-2 alpha on gene expression in both pulmonary artery smooth muscle and endothelial cells. By elucidating whether a mitochondrial dependent oxidant signaling pathway is required for HIF activation and discovering the target genes for HIF-1 alpha and HIF-2 alpha we will provide new molecular information to explain the development of hypoxia induced pulmonary hypertension. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060472-10
Application #
7439160
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Dunsmore, Sarah
Project Start
2000-02-01
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
10
Fiscal Year
2008
Total Cost
$244,061
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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