Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology

Research output: Contribution to journalArticle

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 languageEnglish (US)
JournalChest
Volume128
Issue number6 SUPPL.
DOIs
StatePublished - Dec 2005

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Hypoxia-Inducible Factor 1
Lung
Pulmonary Hypertension
Vascular Endothelial Growth Factor A
Smooth Muscle Myocytes
Endothelial Cells
Vascular Endothelial Growth Factor Receptor
Arterioles
Ventricular Pressure
Heterozygote
Hypertrophy
Cell Biology
Intercellular Signaling Peptides and Proteins
Transcription Factors
Alleles
Cytokines
Genes

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 journalArticle

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