Inhibition of the soluble epoxide hydrolase attenuates monocrotaline- induced pulmonary hypertension in rats

Marc Revermann, Eduardo Barbosa-Sicard, Eva Dony, Ralph T. Schermuly, Christophe Morisseau, Gerd Geisslinger, Ingrid Fleming, Bruce D. Hammock, Ralf P. Brandes

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

OBJECTIVES: The soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to their less active dihydroxy derivatives. Because EETs have anti-inflammatory properties, we determined whether or not inhibition of sEH attenuates disease development in the monocrotaline model of pulmonary hypertension in rats. METHODS: sEH inhibition was achieved using 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (25 mg/l) and cis-4-[4-(3- adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (5 mg/l) administered via drinking water starting 3 days prior to monocrotaline injection (60 mg/kg). RESULTS: Monocrotaline induced the development of progressive pulmonary hypertension. sEH inhibition increased the plasma ratio of EETs to DHETs and attenuated the monocrotaline-induced increase in pulmonary artery medial wall thickness as well as the degree of vascular muscularization. Moreover, right ventricular pressure was significantly lower in the group treated with sEH inhibitors. Pulmonary sEH protein expression and sEH activity, as well as pulmonary cytochrome P450 epoxygenase activity were all impaired in monocrotaline-treated rats as compared with control animals. sEH inhibitors, however, increased the plasma ratio of EETs to dihydroxy epoxyeicosatrienoic acids. Monocrotaline induced the proliferation of pulmonary endothelial and vascular smooth muscle cells in vivo as determined by 5-Bromo-2ĝ€2- deoxy-Uridine incorporation, and this effect was significantly blunted in animals treated with sEH inhibitors. Proliferation of cultured pulmonary smooth muscle cell, however, was not affected by EETs or sEH inhibitors suggesting that the in-vivo effects are a consequence of a direct EET-mediated protection against the inflammation induced by monocrotaline. CONCLUSION: sEH inhibition reduces pulmonary vascular remodeling and the development of pulmonary hypertension in the monocrotaline model of primary pulmonary hypertension in rats.

Original languageEnglish (US)
Pages (from-to)322-331
Number of pages10
JournalJournal of Hypertension
Volume27
Issue number2
DOIs
StatePublished - Feb 2009

Fingerprint

Monocrotaline
Epoxide Hydrolases
Pulmonary Hypertension
Lung
Smooth Muscle Myocytes
Acids
Benzoic Acid
Uridine
Ventricular Pressure
Vascular Smooth Muscle
Drinking Water
Cytochrome P-450 Enzyme System
Pulmonary Artery
Blood Vessels
Anti-Inflammatory Agents

Keywords

  • Epoxyeicosatrienoic acids
  • Lipid mediators
  • Monocrotaline

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Revermann, M., Barbosa-Sicard, E., Dony, E., Schermuly, R. T., Morisseau, C., Geisslinger, G., ... Brandes, R. P. (2009). Inhibition of the soluble epoxide hydrolase attenuates monocrotaline- induced pulmonary hypertension in rats. Journal of Hypertension, 27(2), 322-331. https://doi.org/10.1097/HJH.0b013e32831aedfa

Inhibition of the soluble epoxide hydrolase attenuates monocrotaline- induced pulmonary hypertension in rats. / Revermann, Marc; Barbosa-Sicard, Eduardo; Dony, Eva; Schermuly, Ralph T.; Morisseau, Christophe; Geisslinger, Gerd; Fleming, Ingrid; Hammock, Bruce D.; Brandes, Ralf P.

In: Journal of Hypertension, Vol. 27, No. 2, 02.2009, p. 322-331.

Research output: Contribution to journalArticle

Revermann, M, Barbosa-Sicard, E, Dony, E, Schermuly, RT, Morisseau, C, Geisslinger, G, Fleming, I, Hammock, BD & Brandes, RP 2009, 'Inhibition of the soluble epoxide hydrolase attenuates monocrotaline- induced pulmonary hypertension in rats', Journal of Hypertension, vol. 27, no. 2, pp. 322-331. https://doi.org/10.1097/HJH.0b013e32831aedfa
Revermann, Marc ; Barbosa-Sicard, Eduardo ; Dony, Eva ; Schermuly, Ralph T. ; Morisseau, Christophe ; Geisslinger, Gerd ; Fleming, Ingrid ; Hammock, Bruce D. ; Brandes, Ralf P. / Inhibition of the soluble epoxide hydrolase attenuates monocrotaline- induced pulmonary hypertension in rats. In: Journal of Hypertension. 2009 ; Vol. 27, No. 2. pp. 322-331.
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AU - Barbosa-Sicard, Eduardo

AU - Dony, Eva

AU - Schermuly, Ralph T.

AU - Morisseau, Christophe

AU - Geisslinger, Gerd

AU - Fleming, Ingrid

AU - Hammock, Bruce D.

AU - Brandes, Ralf P.

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N2 - OBJECTIVES: The soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to their less active dihydroxy derivatives. Because EETs have anti-inflammatory properties, we determined whether or not inhibition of sEH attenuates disease development in the monocrotaline model of pulmonary hypertension in rats. METHODS: sEH inhibition was achieved using 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (25 mg/l) and cis-4-[4-(3- adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (5 mg/l) administered via drinking water starting 3 days prior to monocrotaline injection (60 mg/kg). RESULTS: Monocrotaline induced the development of progressive pulmonary hypertension. sEH inhibition increased the plasma ratio of EETs to DHETs and attenuated the monocrotaline-induced increase in pulmonary artery medial wall thickness as well as the degree of vascular muscularization. Moreover, right ventricular pressure was significantly lower in the group treated with sEH inhibitors. Pulmonary sEH protein expression and sEH activity, as well as pulmonary cytochrome P450 epoxygenase activity were all impaired in monocrotaline-treated rats as compared with control animals. sEH inhibitors, however, increased the plasma ratio of EETs to dihydroxy epoxyeicosatrienoic acids. Monocrotaline induced the proliferation of pulmonary endothelial and vascular smooth muscle cells in vivo as determined by 5-Bromo-2ĝ€2- deoxy-Uridine incorporation, and this effect was significantly blunted in animals treated with sEH inhibitors. Proliferation of cultured pulmonary smooth muscle cell, however, was not affected by EETs or sEH inhibitors suggesting that the in-vivo effects are a consequence of a direct EET-mediated protection against the inflammation induced by monocrotaline. CONCLUSION: sEH inhibition reduces pulmonary vascular remodeling and the development of pulmonary hypertension in the monocrotaline model of primary pulmonary hypertension in rats.

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