Abstract
Hypoxia-inducible factor (HIF)-1 is a transcription factor that is activated in response to hypoxia and growth factor/cytokine signaling via regulation of the HIF-1α subunit. HIF-1 has been implicated in the pathogenesis of pulmonary hypertension based on both experimental and clinical data. In a mouse model of pulmonary hypertension, hypoxia-induced increases in right ventricular mass, right ventricular pressure, and medial wall thickness of pulmonary arterioles were impaired in mice that were heterozygous for a null allele at the locus encoding HIF-1α compared to wild-type littermates. Electrophysiologic analyses revealed that the hypoxia-induced hypertrophy and depolarization of pulmonary arterial smooth muscle cells from wild-type mice was significantly impaired in heterozygotes. In clinical studies, immunohistochemical analyses of plexiform lesions within the lungs of patients with severe pulmonary hypertension revealed dramatic overexpression of HIF-1α within proliferating endothelial cells. These cells also expressed vascular endothelial growth factor (VEGF), which is the product of a known HIF-1 target gene, indicating that autocrine VEGF-VEGF receptor signaling may contribution to the pathogenesis of plexiform lesions. These studies implicate HIF-1 in pathophysiologic alterations of both smooth muscle and endothelial cell biology in patients with pulmonary hypertension.
| Original language | English (US) |
|---|---|
| Journal | Chest |
| Volume | 128 |
| Issue number | 6 SUPPL. |
| DOIs | |
| State | Published - Dec 2005 |
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Keywords
- Gene expression
- Hypoxia
- Pulmonary hypertension
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
Cite this
Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology. / Semenza, Gregg L.
In: Chest, Vol. 128, No. 6 SUPPL., 12.2005.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology
AU - Semenza, Gregg L
PY - 2005/12
Y1 - 2005/12
N2 - Hypoxia-inducible factor (HIF)-1 is a transcription factor that is activated in response to hypoxia and growth factor/cytokine signaling via regulation of the HIF-1α subunit. HIF-1 has been implicated in the pathogenesis of pulmonary hypertension based on both experimental and clinical data. In a mouse model of pulmonary hypertension, hypoxia-induced increases in right ventricular mass, right ventricular pressure, and medial wall thickness of pulmonary arterioles were impaired in mice that were heterozygous for a null allele at the locus encoding HIF-1α compared to wild-type littermates. Electrophysiologic analyses revealed that the hypoxia-induced hypertrophy and depolarization of pulmonary arterial smooth muscle cells from wild-type mice was significantly impaired in heterozygotes. In clinical studies, immunohistochemical analyses of plexiform lesions within the lungs of patients with severe pulmonary hypertension revealed dramatic overexpression of HIF-1α within proliferating endothelial cells. These cells also expressed vascular endothelial growth factor (VEGF), which is the product of a known HIF-1 target gene, indicating that autocrine VEGF-VEGF receptor signaling may contribution to the pathogenesis of plexiform lesions. These studies implicate HIF-1 in pathophysiologic alterations of both smooth muscle and endothelial cell biology in patients with pulmonary hypertension.
AB - Hypoxia-inducible factor (HIF)-1 is a transcription factor that is activated in response to hypoxia and growth factor/cytokine signaling via regulation of the HIF-1α subunit. HIF-1 has been implicated in the pathogenesis of pulmonary hypertension based on both experimental and clinical data. In a mouse model of pulmonary hypertension, hypoxia-induced increases in right ventricular mass, right ventricular pressure, and medial wall thickness of pulmonary arterioles were impaired in mice that were heterozygous for a null allele at the locus encoding HIF-1α compared to wild-type littermates. Electrophysiologic analyses revealed that the hypoxia-induced hypertrophy and depolarization of pulmonary arterial smooth muscle cells from wild-type mice was significantly impaired in heterozygotes. In clinical studies, immunohistochemical analyses of plexiform lesions within the lungs of patients with severe pulmonary hypertension revealed dramatic overexpression of HIF-1α within proliferating endothelial cells. These cells also expressed vascular endothelial growth factor (VEGF), which is the product of a known HIF-1 target gene, indicating that autocrine VEGF-VEGF receptor signaling may contribution to the pathogenesis of plexiform lesions. These studies implicate HIF-1 in pathophysiologic alterations of both smooth muscle and endothelial cell biology in patients with pulmonary hypertension.
KW - Gene expression
KW - Hypoxia
KW - Pulmonary hypertension
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UR - http://www.scopus.com/inward/citedby.url?scp=30144441692&partnerID=8YFLogxK
U2 - 10.1378/chest.128.6_suppl.592S
DO - 10.1378/chest.128.6_suppl.592S
M3 - Article
C2 - 16373853
AN - SCOPUS:30144441692
VL - 128
JO - Chest
JF - Chest
SN - 0012-3692
IS - 6 SUPPL.
ER -