title: 20-HETE and CYP4A2 ω-hydroxylase contribute to the elevated blood pressure in hyperandrogenemic female rats.
abstract: In male rats, androgen supplements increase 20-hydroxyeicosatetraenoic acid (20-HETE) via cytochrome P-450 (CYP)4A ω-hydroxylase and cause an increase in blood pressure (BP). In the present study, we determined the roles of 20-HETE and CYP4A2 on the elevated BP in hyperandrogenemic female rats. Chronic dihydrotestosterone (DHT) increased mean arterial pressure (MAP) in female Sprague-Dawley rats (96 ± 2 vs. 108 ± 2 mmHg, P < 0.05) and was associated with increased renal microvascular CYP4A2 mRNA expression (15-fold), endogenous renal 20-HETE (5-fold), and ω-hydroxylase activity (3-fold). Chronic DHT also increased MAP in low salt-fed Dahl salt-resistant female rats (81 ± 4 vs. 95 ± 1 mmHg, P < 0.05) but had no effect on MAP in Dahl salt-sensitive female rats (154 ± 3 vs. 153 ± 3 mmHg), which are known to be 20-HETE deficient. To test the role of CYP4A2, female CYP4A2(-/-) and SS.5(Bn) (wild type) rats were treated with DHT. DHT increased MAP in SS.5(Bn) female rats (104 ± 1 vs. 128 ± 1 mmHg, P < 0.05) but had no effect in CYP4A2(-/-) female rats (118 ± 1 vs. 120 ± 1 mmHg). Renal microvascular 20-HETE was reduced in control CYP4A2(-/-) female rats and was increased with DHT in SS.5(Bn) female rats (6-fold) but not CYP4A2(-/-) female rats. ω-Hydroxylase activity was 40% lower in control CYP4A2(-/-) female rats than in SS.5(Bn) female rats, and DHT decreased ω-hydroxylase activity in SS.5(Bn) female rats (by 50%) but significantly increased ω-hydroxylase activity in CYP4A2(-/-) female rats (3-fold). These data suggest that 20-HETE via CYP4A2 contributes to the elevation in BP in hyperandrogenemic female rats. The data also suggest that 20-HETE synthesis inhibition may be effective in treating the elevated BP in women with hyperandrogenemia, such as women with polycystic ovary syndrome.
authors.affiliation: Department of Physiology, University of Mississippi Medical Center, Jackson, Mississippi; Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Carolina
authors.initials: C
authors.lastname: Dalmasso
authors.affiliation: Department of Physiology, University of Mississippi Medical Center, Jackson, Mississippi; Department of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi; Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Maranon
authors.affiliation: Department of Physiology, University of Mississippi Medical Center, Jackson, Mississippi; Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Chetan
authors.initials: C
authors.lastname: Patil
authors.affiliation: Department of Psychiatry, University of Mississippi Medical Center, Jackson, Mississippi; Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Mohadetheh
authors.initials: M
authors.lastname: Moulana
authors.affiliation: Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi; and Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Damian G
authors.initials: DG
authors.lastname: Romero
authors.affiliation: Department of Physiology, University of Mississippi Medical Center, Jackson, Mississippi; Women's Health Research Center, University of Mississippi Medical Center, Jackson, Mississippi jreckelhoff@umc.edu.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Reckelhoff
mesh_terms: D000728:Androgens / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000633:toxicity; D005260:Female; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006893:Hydroxyeicosatetraenoic Acids / Q000235:genetics / Q000378:metabolism*; D017588:Hyperandrogenism / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D008833:Microcirculation / Q000235:genetics; D051381:Rats; D020303:Rats, Inbred Dahl; D012079:Renal Circulation / Q000235:genetics; D013256:Steroids / Q000097:blood
chemical_list: D000728:Androgens; D006893:Hydroxyeicosatetraenoic Acids; D013256:Steroids; D013196:Dihydrotestosterone; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C465388:cytochrome P-450 CYP4A2 (rat)
keywords: 20-hydroxyeicosatetraenoic acid; CYP4A2−/− rats; Dahl salt-sensitive rats; cytochrome P-450; dihydrotestosterone; polycystic ovary syndrome