Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice

Craig R. Lee, John D. Imig, Matthew L. Edin, Julie Foley, Laura M. DeGraff, J. Alyce Bradbury, Joan P. Graves, Fred B. Lih, James Clark, Page Myers, A. Ligon Perrow, Adrienne N. Lepp, M. Alison Kannon, Oline K. Ronnekleiv, Nabil J. Alkayed, John R. Falck, Kenneth B. Tomer, Darryl C. Zeldin

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

Renal cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) regulate sodium transport and blood pressure. Although endothelial CYP-derived EETs are potent vasodilators, their contribution to the regulation of blood pressure remains unclear. Consequently, we developed transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases to increase endothelial EET biosynthesis. Compared to wild-type littermate controls, an attenuated afferent arteriole constrictor response to endothelin-1 and enhanced dilator response to acetylcholine was observed in CYP2J2 and CYP2C8 transgenic mice. CYP2J2 and CYP2C8 transgenic mice demonstrated modestly, but not significantly, lower mean arterial pressure under basal conditions compared to wild-type controls. However, mean arterial pressure was significantly lower in both CYP2J2 and CYP2C8 transgenic mice during coadministration of N-nitro-L-arginine methyl ester and indomethacin. In a separate experiment, a high-salt diet and subcutaneous angiotensin II was administered over 4 wk. The angiotensin/high-salt-induced increase in systolic blood pressure, proteinuria, and glomerular injury was significantly attenuated in CYP2J2 and CYP2C8 transgenic mice compared to wild-type controls. Collectively, these data demonstrate that increased endothelial CYP epoxygenase expression attenuates afferent arteriolar constrictor reactivity and hypertension-induced increases in blood pressure and renal injury in mice. We conclude that endothelial CYP epoxygenase function contributes to the regulation of blood pressure.

Original languageEnglish (US)
Pages (from-to)3770-3781
Number of pages12
JournalFASEB Journal
Volume24
Issue number10
DOIs
StatePublished - Oct 2010

Keywords

  • CYP2C8
  • CYP2J2
  • EETs
  • Epoxygenase
  • Transgenic

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Lee, C. R., Imig, J. D., Edin, M. L., Foley, J., DeGraff, L. M., Bradbury, J. A., Graves, J. P., Lih, F. B., Clark, J., Myers, P., Perrow, A. L., Lepp, A. N., Kannon, M. A., Ronnekleiv, O. K., Alkayed, N. J., Falck, J. R., Tomer, K. B., & Zeldin, D. C. (2010). Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB Journal, 24(10), 3770-3781. https://doi.org/10.1096/fj.10-160119