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Articles in PresS, published online ahead of print November 9, 2001
J Appl Physiol, 10.1152/jap.00829.2001
Submitted on August 6, 2001
Accepted on October 31, 2001
1 Department of Cell Biology and Physiology, University of New Mexico HSC, Albuquerque, NM, USA
2 Department of Pediatrics, University of New Mexico HSC, Albuquerque, NM, USA; Department of Cell Biology and Physiology, University of New Mexico HSC, Albuquerque, NM, USA
3 Department of Pediatrics, University of New Mexico HSC, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: searley{at}unm.edu.
Nitric oxide (NO) attenuates hypoxia-induced endothelin-1 (ET-1) expression in cultured umbilical vein endothelial cells. We hypothesized that NO similarly attenuates hypoxia-induced increases in ET-1 expression in the lungs of intact animals and reasoned that potentially reduced ET-1 levels may contribute to the protective effects of NO against the development of pulmonary hypertension during chronic hypoxia. As expected, hypoxic exposure (24 hours, 10% O2) increased rat lung ET-1 peptide and preproET-1 mRNA levels. Contrary to our hypothesis, inhaled NO (iNO) did not attenuate hypoxia-induced increases in pulmonary ET-1 peptide or preproET-1 mRNA levels. Due to this surprising finding, we also examined the effects of NO on hypoxia-induced increases in ET peptide levels in cultured cell experiments. Consistent with the results of iNO experiments, administration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) to cultured bovine pulmonary endothelial cells (bPAECs) did not attenuate increases in ET peptide levels resulting from hypoxic (24 hours, 3% O2) exposure. In additional experiments, we examined the effects of NO on the activity of a cloned ET-1 promoter fragment containing a functional hypoxia inducible-1 (HIF-1) binding site in reporter gene experiments. Whereas moderate hypoxia (24 hours, 3% O2) had no effect on ET-1 promoter activity, activity was increased by severe hypoxic (24 hours, 0.5% O2) exposure. ET-1 promoter activity following SNAP administration during severe hypoxia was greater than normoxic controls, although activity was reduced compared to hypoxic controls. These findings suggest that hypoxia-induced pulmonary ET- 1 expression is unaffected by NO.
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