Hypoxia activates Jun-N-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries

N. Jin, N. Hatton, D. R. Swartz, X. L. Xia, Maureen Harrington, S. H. Larsen, R. A. Rhoades

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Chronic alveolar hypoxia is the major cause of pulmonary hypertension. The cellular mechanisms involved in hypoxia-induced pulmonary arterial remodeling are still poorly understood. Mitogen-activated protein kinase (MAPK) is a key enzyme in the signaling pathway leading to cellular growth and proliferation. The purpose of this investigation was to determine the roles that MAPKs, specifically Jun-N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), and p38 kinase, play in the hypoxia-induced pulmonary arterial remodeling. Rats were exposed to normobaric hypoxia (10% O2) for 1, 3, 7, or 14 d. Hypoxia caused significant remodeling in the pulmonary artery characterized by thickening of pulmonary arterial wall and increases in tissue mass and total RNA. JNK, ERK, and p38 kinase tyrosine phosphorylations and their activities were significantly increased by hypoxia. JNK activation peaked at Day 1 and ERK/p38 kinase activation peaked after 7 d of hypoxia. The results from immunohistochemistry show that hypoxia increased phospho-MAPK staining in both large and small intrapulmonary arteries. Hypoxia also upregulated vascular endothelial growth factor messenger RNA (mRNA) and platelet-derived growth factor receptor mRNA levels in pulmonary artery with a time course correlated to the activation of ERK and p38 kinase. The gene expressions of c-jun, c-fos, and egr-1, known as downstream effectors of MAPK, were also investigated. Hypoxia upregulated egr-1 mRNA but downregulated c-jun and c-fos mRNAs. These data suggest that hypoxia-induced activation of JNK is an early response to hypoxic stress and that activation of ERK and p38 kinase appears to be associated with hypoxia-induced pulmonary arterial remodeling.

Original languageEnglish
Pages (from-to)593-601
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume23
Issue number5
StatePublished - 2000

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Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Protein Kinases
Pulmonary Artery
Phosphotransferases
Chemical activation
Mitogen-Activated Protein Kinases
Messenger RNA
Platelet-Derived Growth Factor Receptors
Phosphorylation
Hypoxia
Gene expression
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Rats
RNA
Tissue
Pulmonary Hypertension
Enzymes
Down-Regulation

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology

Cite this

Hypoxia activates Jun-N-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries. / Jin, N.; Hatton, N.; Swartz, D. R.; Xia, X. L.; Harrington, Maureen; Larsen, S. H.; Rhoades, R. A.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 23, No. 5, 2000, p. 593-601.

Research output: Contribution to journalArticle

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