Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids

Zhigang Yu, Fengyun Xu, Linn M. Huse, Christophe Morisseau, Alison J. Draper, John W. Newman, Carol Parker, LeRae Graham, Marguerite M. Engler, Bruce D. Hammock, Darryl C. Zeldin, Deanna L. Kroetz

Research output: Contribution to journalArticle

362 Citations (Scopus)

Abstract

The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.

Original languageEnglish (US)
Pages (from-to)992-998
Number of pages7
JournalCirculation Research
Volume87
Issue number11
StatePublished - Nov 24 2000

Fingerprint

Epoxide Hydrolases
Hydrolysis
Inbred SHR Rats
Acids
Inbred WKY Rats
Blood Pressure
Eicosanoids
Kidney
Blood Vessels
Microsomes
Cytosol
Cytochrome P-450 Enzyme System
Sodium
Hypertension
Water

Keywords

  • Cytochrome P450
  • Dihydroxyeicosatrienoic acids
  • Epoxyeicosatrienoic acids
  • Hypertension
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Yu, Z., Xu, F., Huse, L. M., Morisseau, C., Draper, A. J., Newman, J. W., ... Kroetz, D. L. (2000). Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circulation Research, 87(11), 992-998.

Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. / Yu, Zhigang; Xu, Fengyun; Huse, Linn M.; Morisseau, Christophe; Draper, Alison J.; Newman, John W.; Parker, Carol; Graham, LeRae; Engler, Marguerite M.; Hammock, Bruce D.; Zeldin, Darryl C.; Kroetz, Deanna L.

In: Circulation Research, Vol. 87, No. 11, 24.11.2000, p. 992-998.

Research output: Contribution to journalArticle

Yu, Z, Xu, F, Huse, LM, Morisseau, C, Draper, AJ, Newman, JW, Parker, C, Graham, L, Engler, MM, Hammock, BD, Zeldin, DC & Kroetz, DL 2000, 'Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids', Circulation Research, vol. 87, no. 11, pp. 992-998.
Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW et al. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circulation Research. 2000 Nov 24;87(11):992-998.
Yu, Zhigang ; Xu, Fengyun ; Huse, Linn M. ; Morisseau, Christophe ; Draper, Alison J. ; Newman, John W. ; Parker, Carol ; Graham, LeRae ; Engler, Marguerite M. ; Hammock, Bruce D. ; Zeldin, Darryl C. ; Kroetz, Deanna L. / Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. In: Circulation Research. 2000 ; Vol. 87, No. 11. pp. 992-998.
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abstract = "The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.",
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AU - Draper, Alison J.

AU - Newman, John W.

AU - Parker, Carol

AU - Graham, LeRae

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N2 - The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.

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