Tyrosine kinase receptor activation inhibits NPR-C in lung arterial smooth muscle cells.

Abstract

We have previously demonstrated that expression of the atrial natriuretic peptide (ANP) clearance receptor (NPR-C) is reduced selectively in the lung of rats and mice exposed to hypoxia but not in pulmonary arterial smooth muscle cells (PASMCs) cultured under hypoxic conditions. The current study tested the hypothesis that hypoxia-responsive growth factors, fibroblast growth factors (FGF-1 and FGF-2) and platelet-derived growth factor-BB (PDGF-BB), that activate tyrosine kinase receptors can reduce expression of NPR-C in PASMCs independent of environmental oxygen tension. Growth-arrested rat PASMCs were incubated under hypoxic conditions (1% O2) for 24 h; with FGF-1, FGF-2, or PDGF-BB (0.1-20 ng/ml for 1-24 h); or with ANG II (1-100 nM), endothelin-1 (ET-1, 0.1 microM), ANP (0.1 microM), sodium nitroprusside (SNP, 0.1 microM), or 8-bromo-cGMP (0.1 mM) for 24 h under normoxic conditions. Steady-state NPR-C mRNA levels were assessed by Northern blot analysis. FGF-1, FGF-2, and PDGF-BB induced dose- and time-dependent reduction of NPR-C mRNA expression within 1 h at a threshold concentration of 1 ng/ml; hypoxia, ANG II, ET-1, ANP, SNP, or cGMP did not decrease NPR-C mRNA levels in PASMCs under the above conditions. Downregulation of NPR-C expression by FGF-1, FGF-2, and PDGF-BB was inhibited by the selective FGF-1 receptor tyrosine kinase inhibitor PD-166866 and mitogen-activated protein/extracellular signal-regulated kinase inhibitors U-0126 and PD-98059. These results indicate that activation of tyrosine kinase receptors by hypoxia-responsive growth factors, but neither hypoxia per se nor activation of G protein-coupled receptors, inhibits NPR-C gene expression in PASMCs. These results suggest that FGF-1, FGF-2, and PDGF-BB play a role in the signal transduction pathway linking hypoxia to altered NPR-C expression in lung.

• Authors: J Z Sun, S Oparil, P Lucchesi, J A Thompson, Y F Chen
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 281 Issue 1 Pg. L155-63 (Jul 2001) ISSN: 1040-0605 [Print] United States
• PMID: 11404258 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Receptors, Fibroblast Growth Factor
• Fibroblast Growth Factor 2
• Fibroblast Growth Factor 1
• Receptor Protein-Tyrosine Kinases
• Mitogen-Activated Protein Kinase Kinases
• GTP-Binding Proteins
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor C
• Cyclic GMP

Topics

• Animals
• Cattle (blood)
• Cell Division (drug effects, physiology)
• Cells, Cultured
• Cyclic GMP (pharmacology)
• Down-Regulation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Fetal Blood (physiology)
• Fibroblast Growth Factor 1
• Fibroblast Growth Factor 2 (metabolism, pharmacology)
• GTP-Binding Proteins (physiology)
• Guanylate Cyclase (antagonists & inhibitors)
• Hypoxia (metabolism)
• Male
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Muscle, Smooth, Vascular (cytology, metabolism)
• Pulmonary Artery (cytology, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor Protein-Tyrosine Kinases (physiology)
• Receptors, Atrial Natriuretic Factor (antagonists & inhibitors)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors)