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Departments of 1 Anesthesiology and 3 Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22906-0010; and 2 Center for Medical Genetics, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914
Type II nitric
oxide synthase (NOS) is upregulated in the pulmonary vasculature in a
chronic hypoxia model of pulmonary hypertension. In situ hybridization
analysis demonstrates that type II NOS RNA is increased in the
endothelium as well as in the vascular smooth muscle in the lung. The
current studies examine the role of hypoxia-inducible factor (HIF)-1 in
regulating type II NOS gene expression in response to hypoxia in
pulmonary artery endothelial cells. Northern blot analyses demonstrate
a twofold increase in HIF-1
but not in HIF-1
RNA with hypoxia in
vivo and in vitro. Electrophoretic mobility shift assays show the
induction of specific DNA binding activity when endothelial cells were
subjected to hypoxia. This DNA binding complex was identified as HIF-1
using antibodies directed against HIF-1 and HIF-1. Transient
transfection of endothelial cells resulted in a 2.7-fold increase in
type II NOS promoter activity in response to hypoxia compared with
nonhypoxic controls. Mutation or deletion of the HIF-1 site eliminated
the response to hypoxia. These results demonstrate that HIF-1 is
essential for the hypoxic regulation of type II NOS gene transcription
in pulmonary endothelium.
pulmonary hypertension; gene regulation; nitric oxide; nitric oxide synthase; hypoxia-inducible factor-1
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