on February 27, 2006
Published online before print February 27, 2006, doi: 10.1161/01.HYP.0000208299.62535.58
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Submitted on November 18, 2005
From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute of Biotechnology (P.P., Z.S., P.V., H.G., M.P., D.C., S.J.) and Cardiac Unit (S.J.), University of Leuven, Belgium; Department of Internal Medicine (L.K., F.G.), Justus-Liebig-University, Giessen, Germany; Institute of Cardiovascular Physiology (I.F., E.B.-S., B.F., R.B.), Johann Wolfgang Goethe University, Frankfurt am Main, Germany; Departments of Biochemistry and Pharmacology (J.R.F.), University of Texas Southwestern Medical Center, Dallas; Department of Entomology and Cancer Research Center (B.D.H., I.-H.K.), University of California, Davis; and Department of Nephrology (A.-J.v.Z.), Leiden University Medical Center, Leiden, the Netherlands. * To whom correspondence should be addressed. E-mail: Stefan.janssens{at}med.kuleuven.ac.be.
Abstract--We assessed pulmonary cytochrome P450 (CYP) epoxygenase expression and activity during hypoxia and explored the effects of modulating epoxygenase activity on pulmonary hypertension. The acute hypoxic vasoconstrictor response was studied in Swiss Webster mice, who express CYP2C29 in their lungs. Animals were pretreated with vehicle, the epoxygenase inhibitor (N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide) or an inhibitor of the soluble epoxide hydrolase. Whereas the epoxygenase inhibitor attenuated hypoxic pulmonary constriction (by 52%), the soluble epoxide hydrolase inhibitor enhanced the response (by 39%), indicating that CYP epoxygenase-derived epoxyeicosatrienoic acids elicit pulmonary vasoconstriction. Aerosol gene transfer of recombinant adenovirus containing the human CYP2C9 significantly elevated mean pulmonary artery pressure and total pulmonary resistance indices, both of which were sensitive to the inhibitor sulfaphenazole. The prolonged exposure of mice to hypoxia increased CYP2C29 expression, and transcript levels increased 5-fold after exposure to normobaric hypoxia (FIO2 0.07) for 2 hours. This was followed by a 2-fold increase in protein expression and by a significant increase in epoxyeicosatrienoic acid production after 24 hours. Chronic hypoxia (7 days) elicited pulmonary hypertension and pulmonary vascular remodeling, effects that were significantly attenuated in animals continually treated with N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide (-46% and -55%, respectively). Our results indicate that endogenously generated epoxygenase products are associated with hypoxic pulmonary hypertension in mice and that selective epoxygenase inhibition significantly reduces acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary vascular remodeling. These observations indicate potential novel targets for the treatment of pulmonary hypertension and highlight a pivotal role for CYP epoxygenases in pulmonary responses to hypoxia.
Revised on December 13, 2005
Cytochrome P450 Epoxygenase Gene Function in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling
Peter Pokreisz;
Key words: endothelium-derived factors • arachidonic acids • endothelium-derived factors • lung • remodeling
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