20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension.

Abstract

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14(-/-) mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ± 1 vs. 15 ± 1 μm) and M/L (0.29 ± 0.03 vs. 0.17 ± 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12-20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ± 1 vs. 16 ± 1 μm; M/L: 0.39 ± 0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels.

• Authors: Yan Ding, Cheng-Chia Wu, Victor Garcia, Irina Dimitrova, Adam Weidenhammer, Gregory Joseph, Frank Zhang, Vijay L Manthati, John R Falck, Jorge H Capdevila, Michal L Schwartzman
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 305 Issue 5 Pg. F753-63 (Sep 01 2013) ISSN: 1522-1466 [Electronic] United States
• PMID: 23825080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid
• Hydroxyeicosatetraenoic Acids
• Dihydrotestosterone
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Reserpine

Topics

• Animals
• Blood Pressure (drug effects)
• Dihydrotestosterone
• Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, pharmacology)
• Hypertension (physiopathology)
• Male
• Mice
• Rats
• Rats, Sprague-Dawley
• Renal Artery (drug effects, physiopathology)
• Reserpine (pharmacology)