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)
JournalAmerican Journal of Physiology - Renal Physiology
Volume284
Issue number1 53-1
StatePublished - Jan 1 2003
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Physiology

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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).