Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension

Hypertension is a leading cause of cardiovascular, cerebral, and renal dise ase morbidity and mortality. Here we show that disruption of the Cyp 4a14 g ene causes hypertension, which is, like most human hypertension, more sever e in males. Male Cyp 4a14 (-/-) mice show increases in plasma androgens, ki dney Cyp 4a12 expression. and the formation of prohypertensive 20-hydroxyar achidonate. Castration normalizes the blood pressure of Cyp 4a14 (-/-) mice and minimizes Cyp 4a12 expression and arachidonate omega -hydroxylation, A ndrogen replacement restores hypertensive phenotype, Cyp 4a12 expression, a nd 20-hydroxy-arachidonate formation. We conclude that the androgen-mediate d regulation of Cyp 4a arachidonate monooxygenases is an important componen t of the renal mechanisms that control systemic blood pressures. These resu lts provide direct evidence for a role of Cyp 4a isoforms in cardiovascular physiology. establish Cyp 4a14 (-/-) mice as a monogenic: model for the st udy of cause/effect relationships between blood pressure, sex hormones, and P450 omega -hydroxylases, and suggest the human CYP 4A homologues as candi date genes for the analysis of the genetic and molecular basis of human hyp ertension.