Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice.
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.
Lee
Craig R
CR
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Imig
John D
JD
Edin
Matthew L
ML
Foley
Julie
J
DeGraff
Laura M
LM
Bradbury
J Alyce
JA
Graves
Joan P
JP
Lih
Fred B
FB
Clark
James
J
Myers
Page
P
Perrow
A Ligon
AL
Lepp
Adrienne N
AN
Kannon
M Alison
MA
Ronnekleiv
Oline K
OK
Alkayed
Nabil J
NJ
Falck
John R
JR
Tomer
Kenneth B
KB
Zeldin
Darryl C
DC
D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure; D015153:Blotting, Western; D002478:Cells, Cultured; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D005260:Female; D006973:Hypertension / Q000150:complications*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007674:Kidney Diseases / Q000209:etiology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
C000717350:CYP2J2 protein, human; D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2