Cardiovascular Research Advance Access first published online on August 13, 2009
This version [Corrected Proof] published online on September 4, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp281
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Hypoxia-induced pulmonary hypertension: comparison of soluble epoxide hydrolase deletion vs. inhibition
1 Institute for Vascular Signalling, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
2 University of Giessen Lung Center, Department of Internal Medicine II/V, Justus-Liebig-University Giessen, Giessen, Germany
3 Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Bad Nauheim, Germany
4 Department of Entomology, University of California, Davis, CA, USA
* Corresponding author. Tel: +49 69 6301 6972, Fax: +49 69 6301 7668, Email: fleming{at}em.uni-frankfurt.de
Aims: 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% O2) for 21 days in wild-type (WT) and sEH–/– mice and compared the effects with chronic (4 months) sEH inhibition.
Methods and 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.
Conclusion: 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.
KEYWORDS Cytochrome P450; Epoxyeicosatrienoic acid; Hypoxia; Pulmonary hypertension; Soluble epoxide hydrolase
Time for primary review: 23 days