title: Hypoxia-induced pulmonary hypertension: comparison of soluble epoxide hydrolase deletion vs. inhibition.
abstract: OBJECTIVE
  The C-terminal domain of the soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to their less active diols, while the N-terminal domain demonstrates lipid phosphatase activity. As EETs are potent vasoconstrictors in the pulmonary circulation, we assessed the development of pulmonary hypertension induced by exposure to hypoxia (10% O(2)) for 21 days in wild-type (WT) and sEH(-/-) mice and compared the effects with chronic (4 months) sEH inhibition.
  
  
  RESULTS
  In isolated lungs from WT mice, acute hypoxic vasoconstriction (HPV) was potentiated by sEH inhibition and attenuated by an EET antagonist. After prolonged hypoxia, the acute HPV and sensitivity to the EET antagonist were increased, but potentiation of vasoconstriction following sEH inhibition was not evident. Chronic hypoxia also stimulated the muscularization of pulmonary arteries and decreased sEH expression in WT mice. In normoxic sEH(-/-) mice, acute HPV and small artery muscularization were greater than that in WT lungs and enhanced muscularization was accompanied with decreased voluntary exercise capacity. Acute HPV in sEH(-/-) mice was insensitive to sEH inhibition but inhibited by the EET antagonist and chronic hypoxia induced an exaggerated pulmonary vascular remodelling. In WT mice, chronic sEH inhibition increased serum EET levels but failed to affect acute HPV, right ventricle weight, pulmonary artery muscularization, or voluntary running distance. In human donor lungs, the sEH was expressed in the wall of pulmonary arteries, however, sEH expression was absent in samples from patients with pulmonary hypertension.
  
  
  CONCLUSIONS
  These data suggest that a decrease in sEH expression is intimately linked to pathophysiology of hypoxia-induced pulmonary remodelling and hypertension. However, as sEH inhibitors do not promote the development of pulmonary hypertension it seems likely that the N-terminal lipid phosphatase may play a role in the development of this disease.
authors.affiliation: Institute for Vascular Signalling, Johann Wolfgang Goethe University, D-60590 Frankfurt am Main, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Keserü
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barbosa-Sicard
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Tanaka
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Beate
authors.initials: B
authors.lastname: Fisslthaler
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology*; D000860:Hypoxia / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic; D014661:Vasoconstriction
chemical_list: D004851:Epoxide Hydrolases
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