Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries
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 Ca(2+)-activated K(+) channels in vascular smooth muscle cells and thereby may modulate vascular reactivity. We transfected renal inter...
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Published in | American journal of physiology. Renal physiology Vol. 284; no. 1; pp. F51 - F56 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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01.01.2003
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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 Ca(2+)-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-K(m) arachidonic acid omega-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 EC(50) from 0.37 +/- 0.04 microM in plasmid-transfected arteries to 0.07 +/- 0.01 microM 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. |
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AbstractList | 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 Ca
2+
-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- K
m
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 EC
50
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. 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 Ca(2+)-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-K(m) arachidonic acid omega-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 EC(50) from 0.37 +/- 0.04 microM in plasmid-transfected arteries to 0.07 +/- 0.01 microM 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. |
Author | Kaide, Jun-Ichi Wang, Ji-Shi Wang, Mong-Heng Falck, John R Nasjletti, Alberto Laniado-Schwartzman, Michal Zhang, Fan Gopal, V Raj |
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Cites_doi | 10.1111/j.1469-7793.1998.771bs.x 10.1172/JCI119279 10.1161/01.HYP.35.1.307 10.1152/ajpheart.1994.266.5.H1879 10.1161/01.HYP.33.1.414 10.1074/jbc.272.43.27345 10.1152/ajpheart.1998.274.1.H27 10.1152/ajpregu.1996.270.1.R217 10.1152/ajpheart.1994.266.5.H2098 10.1152/ajprenal.1999.277.5.F790 10.1152/ajprenal.1999.276.2.F246 10.1152/ajprenal.1994.266.2.F275 10.1152/ajpregu.1998.274.1.R52 10.1152/ajpregu.1996.270.1.R228 10.1038/ki.1997.234 10.1161/01.RES.83.11.1069 10.1073/pnas.95.21.12701 10.1111/j.1476-5381.1992.tb14327.x 10.1161/01.RES.68.4.1154 10.1161/01.RES.72.1.126 10.1161/hy1201.096116 10.1152/ajprenal.00265.2001 10.1042/cs0980277 10.1152/ajpregu.1999.276.6.R1691 10.1152/ajplung.1997.272.5.L823 |
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References | Laniado-Schwartzman M (B16) 1989; 264 B20 B21 B22 B23 B24 B26 B27 Wang MH (B25) 1998; 284 B28 B29 B10 B11 B12 B13 Carroll MA (B4) 1992; 260 B14 B15 B17 B18 B19 B1 B2 B3 B5 B7 B8 B9 Escalante B (B6) 1988; 248 |
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Snippet | 20-HETE, a cytochrome P-450 4A (CYP4A1)-derived arachidonic acid metabolite, is a major eicosanoid formed in renal and extrarenal microcirculation. 20-HETE... |
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SubjectTerms | Amides - pharmacology Animals Arachidonic Acid - metabolism Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 Family 4 DNA, Complementary Gene Expression - physiology Hydroxyeicosatetraenoic Acids - metabolism Microcirculation - drug effects Microcirculation - physiology Phenylephrine - pharmacology Rats Rats, Sprague-Dawley Renal Artery - physiology Renal Circulation - drug effects Renal Circulation - physiology Sulfones - pharmacology Transfection Vasoconstrictor Agents - pharmacology |
Title | Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries |
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