Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries

Jun Ichi Kaide, Mong Heng Wang, Ji Shi Wang, Fan Zhang, V. Raj Gopal, John R. Falck, Alberto Nasjletti, Michal Laniado-Schwartzman

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

20-HETE, a cytochrome P-450 4A (CYP4A1)-derived arachidonic acid metabolite, is a major eicosanoid formed in renal and extrarenal microcirculation. 20-HETE inhibits Ca2+-activated K+ channels in vascular smooth muscle cells and thereby may modulate vascular reactivity. We transfected renal interlobar arteries with an expression plasmid containing the cDNA of CYP4A1, the low-Km arachidonic acid ω-hydroxylase, and examined the consequences of increasing 20-HETE synthesis on constrictor responses to phenylephrine. CYP4A1-transfected interlobar arteries demonstrated a twofold increase in CYP4A protein levels and 20-HETE production compared with arteries transfected with the empty plasmid; they also showed increased sensitivity to phenylephrine, as evidenced by a decrease in EC50 from 0.37 ± 0.04 μM in plasmid-transfected arteries to 0.07 ± 0.01 μM in CYP4A1-transfected arteries. The increased sensitivity to phenylephrine was greatly attenuated by N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), a selective inhibitor of 20-HETE synthesis, and by 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, a specific 20-HETE antagonist. This effect of DDMS was reversed by addition of 20-HETE, further substantiating the notion that increased levels of 20-HETE contribute to the increased sensitivity to phenylephrine in vessels overexpressing CYP4A1. These data suggest that 20-HETE of vascular origin sensitizes renal vascular smooth muscle to phenylephrine.

Original languageEnglish (US)
Pages (from-to)F51-F56
JournalAmerican Journal of Physiology - Renal Physiology
Volume284
Issue number1 53-1
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

Keywords

  • 20-hydroxyeicosatetraenoic acid
  • Arachidonic acid
  • Cytochrome P-450
  • Phenylephrine

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Kaide, J. I., Wang, M. H., Wang, J. S., Zhang, F., Gopal, V. R., Falck, J. R., Nasjletti, A., & Laniado-Schwartzman, M. (2003). Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries. American Journal of Physiology - Renal Physiology, 284(1 53-1), F51-F56. https://doi.org/10.1152/ajprenal.00249.2002