Cytochrome P450 epoxygenase gene function in hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling.
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.
Pokreisz
Peter
P
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute of Biotechnology, University of Leuven, Belgium.
Fleming
Ingrid
I
Kiss
Ladislau
L
Barbosa-Sicard
Eduardo
E
Fisslthaler
Beate
B
Falck
John R
JR
Hammock
Bruce D
BD
Kim
In-Hae
IH
Szelid
Zsolt
Z
Vermeersch
Pieter
P
Gillijns
Hilde
H
Pellens
Marijke
M
Grimminger
Friedrich
F
van Zonneveld
Anton-Jan
AJ
Collen
Desire
D
Busse
Rudi
R
Janssens
Stefan
S
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
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