Hypoxia-induced pulmonary hypertension: Comparison of soluble epoxide hydrolase deletion vs. inhibition

Benjamin Keserü, Eduardo Barbosa-Sicard, Ralph T. Schermuly, Hiromasa Tanaka, Bruce D. Hammock, Norbert Weissmann, Beate Fisslthaler, Ingrid Fleming

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

AimsThe 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 O2) for 21 days in wild-type (WT) and sEH-/- mice and compared the effects with chronic (4 months) sEH inhibition.Methods and resultsIn 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.ConclusionThese 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.

Original languageEnglish (US)
Pages (from-to)232-240
Number of pages9
JournalCardiovascular Research
Volume85
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Epoxide Hydrolases
Pulmonary Hypertension
Vasoconstriction
Pulmonary Artery
Lung
Hypoxia
Phosphoric Monoester Hydrolases
Lipids
Pulmonary Circulation
Vasoconstrictor Agents
Running

Keywords

  • Cytochrome P450
  • Epoxyeicosatrienoic acid
  • Hypoxia
  • Pulmonary hypertension
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Keserü, B., Barbosa-Sicard, E., Schermuly, R. T., Tanaka, H., Hammock, B. D., Weissmann, N., ... Fleming, I. (2010). Hypoxia-induced pulmonary hypertension: Comparison of soluble epoxide hydrolase deletion vs. inhibition. Cardiovascular Research, 85(1), 232-240. https://doi.org/10.1093/cvr/cvp281

Hypoxia-induced pulmonary hypertension : Comparison of soluble epoxide hydrolase deletion vs. inhibition. / Keserü, Benjamin; Barbosa-Sicard, Eduardo; Schermuly, Ralph T.; Tanaka, Hiromasa; Hammock, Bruce D.; Weissmann, Norbert; Fisslthaler, Beate; Fleming, Ingrid.

In: Cardiovascular Research, Vol. 85, No. 1, 01.2010, p. 232-240.

Research output: Contribution to journalArticle

Keserü, B, Barbosa-Sicard, E, Schermuly, RT, Tanaka, H, Hammock, BD, Weissmann, N, Fisslthaler, B & Fleming, I 2010, 'Hypoxia-induced pulmonary hypertension: Comparison of soluble epoxide hydrolase deletion vs. inhibition', Cardiovascular Research, vol. 85, no. 1, pp. 232-240. https://doi.org/10.1093/cvr/cvp281
Keserü B, Barbosa-Sicard E, Schermuly RT, Tanaka H, Hammock BD, Weissmann N et al. Hypoxia-induced pulmonary hypertension: Comparison of soluble epoxide hydrolase deletion vs. inhibition. Cardiovascular Research. 2010 Jan;85(1):232-240. https://doi.org/10.1093/cvr/cvp281
Keserü, Benjamin ; Barbosa-Sicard, Eduardo ; Schermuly, Ralph T. ; Tanaka, Hiromasa ; Hammock, Bruce D. ; Weissmann, Norbert ; Fisslthaler, Beate ; Fleming, Ingrid. / Hypoxia-induced pulmonary hypertension : Comparison of soluble epoxide hydrolase deletion vs. inhibition. In: Cardiovascular Research. 2010 ; Vol. 85, No. 1. pp. 232-240.
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