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1 Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
2 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
3 Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: barbara.meyrick{at}mcmail.vanderbilt.edu.
We examined the hypothesis that the potent vasoconstrictor, endothelin-1(ET-1) regulates both its own production and production of the vasodilator prostaglandins, PGE2 and prostacyclin, in sheep peripheral lung vascular smooth muscle cells (PLVSMC). Confluent layers of PLVSMC were exposed to 10 nM ET-1 and expression of the ppET-1, COX-1 and COX-2 genes was examined by RT-PCR and Western analysis. Intracellular levels of ET-1 were measured by ELISA with and without addition of the protein synthesis inhibitor, Brefeldin A (50 :g/ml). Prostaglandin levels were measured by GC/MS. Through use of ETA and ETB antagonists (BQ-610 and BQ-788, respectively), the contribution of the endothelin receptors to COX-1 and COX-2 expression and ppET-1 gene expression was examined. The contribution of phosphorylated p-38 and p44/42 MAPK on COX-1 and COX-2 expression was also examined using the MAPK inhibitors (p-38, SB203580 and p44/42, PD98056). ET-1 resulted in transient increases in ppET-1, COX-1 and COX-2 gene and protein expression and release of 6-keto PGF1
and PGE2 (p <0.05). Both internalization of ET-1 and synthesis of new peptide contributed to an increase in intracellular ET-1 (p <0.05). Although increased ppET-1 was regulated by both ETA and ETB, COX-2 expression was upregulated only by ETA: COX-1 expression was unaffected by either antagonist. ET-1 treatment resulted in transient phosphorylation of p-38 and p-44/42 MAPK and inhibitors of these MAPKs suppressed expression of COX-2, but not COX-1. Our data indicate that local production of ET-1 regulates the COX-2 by activation of the ETA receptor and phosphorylation of the p-38 and p-44/42 MAPK in PLVSMC.
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