title: Cytochrome P450 epoxygenase gene function in hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling.
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.
authors.affiliation: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute of Biotechnology, University of Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Pokreisz
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Ladislau
authors.initials: L
authors.lastname: Kiss
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barbosa-Sicard
authors.forename: Beate
authors.initials: B
authors.lastname: Fisslthaler
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szelid
authors.forename: Pieter
authors.initials: P
authors.lastname: Vermeersch
authors.forename: Hilde
authors.initials: H
authors.lastname: Gillijns
authors.forename: Marijke
authors.initials: M
authors.lastname: Pellens
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Anton-Jan
authors.initials: AJ
authors.lastname: van Zonneveld
authors.forename: Desire
authors.initials: D
authors.lastname: Collen
authors.forename: Rudi
authors.initials: R
authors.lastname: Busse
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssens
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001808:Blood Vessels / Q000503:physiopathology; D002908:Chronic Disease; D065729:Cytochrome P-450 CYP2C9; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000201:enzymology; D051379:Mice; D010105:Oxygenases / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D000577:Amides; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C086292:Cyp2c29 protein, mouse; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2