Androgen-Induced Hypertension in Angiotensinogen Deficient Mice: Role of 20-HETE and EETS

Authors

Victor Garcia, Department of Pharmacology, New York Medical College, Valhalla, NY, United States. Electronic address: Victor_Garcia@nymc.edu.
Jennifer Cheng, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
Adam Weidenhammer, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
Yan Ding, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
Cheng-Chia Wu, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
Fan Zhang, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
Katherine Gotlinger, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.
John R. Falck, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Michal L. Schwartzman, Department of Pharmacology, New York Medical College, Valhalla, NY, United States.

Author Type(s)

Faculty

DOI

10.1016/j.prostaglandins.2014.12.001

Journal Title

Prostaglandins & Other Lipid Mediators

First Page

124

Last Page

30

Document Type

Article

Publication Date

1-1-2015

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.

Recommended Citation

Garcia, V., Cheng, J., Weidenhammer, A., Ding, Y., Wu, C., Zhang, F., Gotlinger, K., Falck, J. R., & Schwartzman, M. L. (2015). Androgen-Induced Hypertension in Angiotensinogen Deficient Mice: Role of 20-HETE and EETS. Prostaglandins & Other Lipid Mediators, 116-117, 124-30. https://doi.org/10.1016/j.prostaglandins.2014.12.001