Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension.
Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality. Here we show that disruption of the Cyp 4a14 gene causes hypertension, which is, like most human hypertension, more severe in males. Male Cyp 4a14 (-/-) mice show increases in plasma androgens, kidney Cyp 4a12 expression, and the formation of prohypertensive 20-hydroxyarachidonate. Castration normalizes the blood pressure of Cyp 4a14 (-/-) mice and minimizes Cyp 4a12 expression and arachidonate omega-hydroxylation. Androgen replacement restores hypertensive phenotype, Cyp 4a12 expression, and 20-hydroxy-arachidonate formation. We conclude that the androgen-mediated regulation of Cyp 4a arachidonate monooxygenases is an important component of the renal mechanisms that control systemic blood pressures. These results provide direct evidence for a role of Cyp 4a isoforms in cardiovascular physiology, establish Cyp 4a14 (-/-) mice as a monogenic model for the study of cause/effect relationships between blood pressure, sex hormones, and P450 omega-hydroxylases, and suggest the human CYP 4A homologues as candidate genes for the analysis of the genetic and molecular basis of human hypertension.
Holla
V R
VR
Department of Medicine, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Adas
F
F
Imig
J D
JD
Zhao
X
X
Price
E
E
Olsen
N
N
Kovacs
W J
WJ
Magnuson
M A
MA
Keeney
D S
DS
Breyer
M D
MD
Falck
J R
JR
Waterman
M R
MR
Capdevila
J H
JH
D000728:Androgens / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001794:Blood Pressure; D002369:Castration; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012079:Renal Circulation / Q000502:physiology; D012727:Sex Characteristics; D013739:Testosterone / Q000494:pharmacology; D014655:Vascular Resistance
D000728:Androgens; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D016718:Arachidonic Acid; D013739:Testosterone; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C067516:arachidonic acid 18-hydroxylase; D042926:Cytochrome P-450 CYP4A