title: Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20-HETE synthase.
abstract: Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5α-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(-/-) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20-HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20-HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine-mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgen-induced hypertension and can cause hypertension independent of androgen.
authors: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors: Cheng-Chia
authors: CC
authors: Wu
authors: Shaojun
authors: S
authors: Mei
authors: Jennifer
authors: J
authors: Cheng
authors: Yan
authors: Y
authors: Ding
authors: Adam
authors: A
authors: Weidenhammer
authors: Victor
authors: V
authors: Garcia
authors: Fan
authors: F
authors: Zhang
authors: Katherine
authors: K
authors: Gotlinger
authors: Vijaya L
authors: VL
authors: Manthati
authors: John R
authors: JR
authors: Falck
authors: Jorge H
authors: JH
authors: Capdevila
authors: Michal L
authors: ML
authors: Schwartzman
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D015854:Up-Regulation
chemical_list: D000728:Androgens; D006893:Hydroxyeicosatetraenoic Acids; D013196:Dihydrotestosterone; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C493210:Cyp4a12a protein, mouse; D000072470:Cytochrome P450 Family 4
references: Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1089-95
references: 15130884
references: Trends Endocrinol Metab. 2010 Aug;21(8):496-503
references: 20381374
references: Hypertension. 2001 May;37(5):1199-208
references: 11358929
references: Am J Physiol Regul Integr Comp Physiol. 2001 Jan;280(1):R255-61
references: 11124159
references: Am J Physiol Renal Physiol. 2009 Oct;297(4):F875-84
references: 19675180
references: J Biol Chem. 1989 Jul 15;264(20):11658-62
references: 2501294
references: Biochem J. 2007 Apr 1;403(1):109-18
references: 17112342
references: Physiol Genomics. 2007 Jun 19;30(1):74-81
references: 17341693
references: Hypertension. 2011 Apr;57(4):788-94
references: 21321301
references: Pharmacogenetics. 2004 Jan;14(1):1-18
references: 15128046
references: J Hypertens. 2011 Mar;29(3):501-8
references: 21150635
references: Exp Biol Med (Maywood). 2010 Nov;235(11):1365-74
references: 20943934
references: Kidney Blood Press Res. 2008;31(2):71-9
references: 18319594
references: J Hypertens. 1993 Oct;11(10):1031-8
references: 8258666
references: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R60-8
references: 12069931
references: J Biol Chem. 2000 Feb 11;275(6):4118-26
references: 10660572
references: Hypertension. 1987 Jun;9(6 Pt 2):III130-6
references: 3596779
references: Hypertension. 2000 Oct;36(4):604-9
references: 11040243
references: Am J Physiol. 1994 Jun;266(6 Pt 1):C1775-82
references: 8023907
references: Biochem Pharmacol. 2008 Jun 15;75(12):2263-75
references: 18433732
references: Gend Med. 2008;5 Suppl A:S114-20
references: 18395677
references: Pharmacol Rep. 2008 Jan-Feb;60(1):29-37
references: 18276983
references: J Clin Invest. 2006 Jun;116(6):1696-702
references: 16691295
references: Hypertension. 2007 Jul;50(1):123-9
references: 17548721
references: Hypertension. 2008 May;51(5):1393-8
references: 18391101
references: Am J Physiol. 1998 Oct;275(4):F565-75
references: 9755128
references: Acta Endocrinol (Copenh). 1991 Jan;124(1):91-7
references: 2000704
references: Hypertension. 2000 Jan;35(1 Pt 2):457-63
references: 10642341
references: Hypertension. 1995 Mar;25(3):305-13
references: 7875754
references: Am J Physiol Regul Integr Comp Physiol. 2003 Apr;284(4):R1055-62
references: 12531784
references: J Am Soc Nephrol. 2008 Aug;19(8):1606-12
references: 18385420
references: Hypertension. 1997 Jan;29(1 Pt 2):494-9
references: 9039148
references: Am J Physiol. 1998 Feb;274(2):F395-404
references: 9486235
references: Circulation. 2005 Jan 4;111(1):63-9
references: 15611369
references: Circ Res. 1993 Jan;72(1):126-36
references: 8417836
references: Circ Res. 2006 Apr 14;98(7):962-9
references: 16543501
references: J Cardiovasc Pharmacol. 2010 Oct;56(4):336-44
references: 20930591
references: Hypertension. 1991 Jun;17(6 Pt 1):776-9
references: 2045139
references: Hypertension. 2010 Nov;56(5):871-8
references: 20837888
references: Am J Med Sci. 1994 Mar;307(3):173-81
references: 8160707
references: Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1543-8
references: 21474427
references: Endocr Rev. 2003 Jun;24(3):313-40
references: 12788802
references: Prostaglandins Other Lipid Mediat. 2012 May;98(1-2):31-6
references: 22484021
references: Biochem J. 1997 Aug 1;325 ( Pt 3):741-9
references: 9271096
references: Nephron Physiol. 2009;113(4):p23-8
references: 19713718
references: Hypertension. 2000 Jan;35(1 Pt 2):480-3
references: 10642345
references: Gen Pharmacol. 1997 Mar;28(3):351-9
references: 9068972
references: Kidney Int. 2009 Jun;75(12):1288-1296
references: 19279555
references: Hypertension. 2001 Dec 1;38(6):1311-5
references: 11751709
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5211-6
references: 11320253
references: Science. 1989 Jan 20;243(4889):388-90
references: 2492116
references: Am J Physiol Renal Physiol. 2000 Jun;278(6):F949-53
references: 10836982
references: Am J Physiol. 1999 Feb;276(2):F246-53
references: 9950955
references: Eur J Pharmacol. 1993 Apr 22;235(1):1-7
references: 8519270
references: Am J Hypertens. 2001 Jun;14(6 Pt 2):90S-97S
references: 11411771
references: Free Radic Biol Med. 2005 Apr 15;38(8):1032-6
references: 15780761
references: Hypertension. 2004 May;43(5):918-23
references: 15023933
references: Am J Physiol. 1992 Apr;262(4 Pt 2):F591-9
references: 1566872
references: Hypertension. 1993 Sep;22(3):357-64
references: 8349328
references: Am J Physiol Regul Integr Comp Physiol. 2007 Jun;292(6):R2400-5
references: 17303679