title: Androgen-induced hypertension in angiotensinogen deficient mice: role of 20-HETE and EETS.
abstract: 20-HETE is a potent inducer of endothelial ACE in vitro and administration of lisinopril or losartan attenuates blood pressure in models of 20-HETE-dependent hypertension. The present study was undertaken to further define the relationship between 20-HETE and the renin-angiotensin system in hypertension using an angiotensinogen-deficient mouse (Agt+/-). Treatment of male AGT+/- with 5α-dihydrotestosterone (DHT) increased systolic BP from 102±2 to 125±3mmHg; in comparison, the same treatment raised BP in wild type (WT) from 110±2 to 138±2mmHg. DHT increased vascular 20-HETE levels in AGT+/- and WT from 1.5±0.7 and 2.1±0.6 to 13.0±2.0 and 15.8±4.0ng/mg, respectively. Concurrent treatment with the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented the increases in BP in both AGT+/- and WT mice. Administration of 20-HEDE at the peak of the DHT-induced BP increase (12 days) reduced BP to basal levels after 48h. Interestingly, basal levels of renal microvascular EETs were higher in AGT+/- compared to WT (55.2±9.7 vs 20.0±4.1ng/mg) and treatment of AGT+/- with DHT decreased the levels of EETs (28.4±5.1ng/mg). DHT-mediated changes in vascular EET level were not observed in WT mice. Vascular Cyp4a12 and ACE protein levels were increased in both AGT+/- and WT by 30-40% and decreased with concomitant administration of 20-HEDE. Lisinopril was as effective as 20-HEDE in preventing DHT-mediated increases in BP in both AGT+/- and WT mice. This study substantiates our previous findings that the RAS plays an important role in 20-HETE-mediated hypertension. It also proposes a novel interaction between 20-HETE and EETs.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States. Electronic address: Victor_Garcia@nymc.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Weidenhammer
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Gotlinger
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
mesh_terms: D000728:Androgens / Q000009:adverse effects* / Q000494:pharmacology; D000809:Angiotensins / Q000172:deficiency*; D000818:Animals; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains
chemical_list: C494667:20-hydroxyeicosa-6(Z),15(Z)-dienoic acid; D000728:Androgens; D000809:Angiotensins; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid
keywords: 20-HETE; ACE; Androgen; Angiotensinogen; Hypertension