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

被引:23
作者
Ding, Yan [1 ]
Wu, Cheng-Chia [1 ]
Garcia, Victor [1 ]
Dimitrova, Irina [1 ]
Weidenhammer, Adam [1 ]
Joseph, Gregory [1 ]
Zhang, Frank [1 ]
Manthati, Vijay L. [2 ]
Falck, John R. [2 ]
Capdevila, Jorge H. [3 ]
Schwartzman, Michal L. [1 ]
机构
[1] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[3] Vanderbilt Univ, Dept Med & Biochem, Nashville, TN 37235 USA
基金
美国国家卫生研究院;
关键词
20-hydroxyeicosatetraenoic acid; cytochrome P-450 4A; blood pressure; androgen; 20-HYDROXYEICOSATETRAENOIC ACID SYNTHESIS; ANGIOTENSIN-II; ENDOTHELIAL DYSFUNCTION; VASCULAR DYSFUNCTION; OXIDATIVE STRESS; ACTIVATION; CONTRIBUTES; INDUCTION; EXCRETION; APOPTOSIS;
D O I
10.1152/ajprenal.00292.2013
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 5 alpha-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 mu m) 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 mu m; 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.
引用
收藏
页码:F753 / F763
页数:11
相关论文
共 43 条
[21]   Androgen-mediated induction of the kidney arachidonate hydroxylases is associated with the development of hypertension [J].
Nakagawa, K ;
Marji, JS ;
Schwartzman, ML ;
Waterman, MR ;
Capdevila, JH .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2003, 284 (04) :R1055-R1062
[22]   20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells [J].
Nilakantan, Vani ;
Maenpaa, Cheryl ;
Jia, Guangfu ;
Roman, Richard J. ;
Park, Frank .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2008, 294 (03) :F562-F570
[23]   Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension [J].
Oyekan, AO ;
McAward, K ;
Conetta, J ;
Rosenfeld, L ;
McGiff, JC .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 1999, 276 (03) :R766-R775
[24]   20-hydroxyeicosatetraenoic acid mediates angiotensin II-induced phospholipase D activation in vascular smooth muscle cells [J].
Parmentier, JH ;
Muthalif, MM ;
Nishimoto, AT ;
Malik, KU .
HYPERTENSION, 2001, 37 (02) :623-629
[25]   Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment [J].
Schiffrin, EL .
AMERICAN JOURNAL OF HYPERTENSION, 2004, 17 (12) :1192-1200
[26]   From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension [J].
Schiffrin, EL ;
Touyz, RM .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2004, 287 (02) :H435-H446
[27]   Cytochrome P450-derived eicosanoids and vascular dysfunction in coronary artery disease patients [J].
Schuck, Robert N. ;
Theken, Katherine N. ;
Edin, Matthew L. ;
Caughey, Melissa ;
Bass, Almasa ;
Ellis, Kyle ;
Tran, Bryant ;
Steele, Savanna ;
Simmons, Brian P. ;
Lih, Fred B. ;
Tomer, Kenneth B. ;
Wu, Michael C. ;
Hinderliter, Alan L. ;
Stouffer, George A. ;
Zeldin, Darryl C. ;
Lee, Craig R. .
ATHEROSCLEROSIS, 2013, 227 (02) :442-448
[28]   Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension [J].
Singh, Harpreet ;
Cheng, Jennifer ;
Deng, Huan ;
Kemp, Rowena ;
Ishizuka, Tsuneo ;
Nasjletti, Alberto ;
Schwartzman, Michal Laniado .
HYPERTENSION, 2007, 50 (01) :123-129
[29]   CYP4A2-Induced Hypertension Is 20-Hydroxyeicosatetraenoic Acid- and Angiotensin II-Dependent [J].
Sodhi, Komal ;
Wu, Cheng-Chia ;
Cheng, Jennifer ;
Gotlinger, Katherine ;
Inoue, Kazuyoshi ;
Goli, Mohan ;
Falck, John R. ;
Abraham, Nader G. ;
Schwartzman, Michal L. .
HYPERTENSION, 2010, 56 (05) :871-U297
[30]   20-hydroxyeicosatetraenoic acid (20-HETE) stimulates migration of vascular smooth muscle cells [J].
Stec, David E. ;
Gannon, Kimberly P. ;
Beaird, Janis S. ;
Drummond, Heather A. .
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 2007, 19 (1-4) :121-128