1Department of Pharmacology, New York Medical College, 15 Dana Road, BSB Rm. 530, Valhalla, NY 10595, USA.
Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F753-63. doi: 10.1152/ajprenal.00292.2013. Epub 2013 Jul 3.
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.
20-羟二十碳四烯酸（20-HETE）是一种细胞色素 P-450（Cyp）衍生的花生四烯酸代谢物，已被证明可增加平滑肌收缩和增殖，刺激内皮功能障碍和激活，并促进高血压。我们研究了 20-HETE 是否有助于高血压中的微血管重塑。在 Sprague-Dawley 大鼠中，给予 20-HETE 生物合成抑制剂 HET0016 或 20-HETE 拮抗剂 N-20-羟二十碳六烯酸（20-HEDE）可预防 5α-二氢睾酮（DHT）诱导的血压升高，并消除 DHT 诱导的肾叶间动脉中腔比（M/L）、中膜厚度和胶原 IV 沉积的增加。利血平可预防 DHT 处理大鼠的血压升高，但不影响微血管重塑（M/L、中膜厚度和胶原沉积）；在这些条件下，20-HETE 拮抗剂的治疗减轻了微血管重塑，表明 20-HETE 有助于独立于血压升高的 DHT 诱导的血管重塑。在 Cyp4a14（-/-）小鼠中，其表现出雄激素驱动和 20-HETE 依赖性高血压，用 20-HETE 拮抗剂治疗可消除肾阻力动脉重塑的测量，即中膜厚度（24±1μm 对 15±1μm）和 M/L（0.29±0.03μm 对 0.17±0.01μm）。此外，在 Cyp4a12 转基因小鼠中，Cyp4a12-20-HETE 合酶的表达受四环素敏感启动子驱动，用强力霉素治疗导致血压升高（140±4mmHg 对 92±5mmHg）和肾阻力动脉重塑显著增加（中膜厚度：23±1μm 对 16±1μm；M/L：0.39±0.04μm 对 0.23±0.02μm）；这些增加被 20-HEDE 共同治疗所消除。这项研究表明，20-HETE 是高血压中小血管重塑的关键调节剂；其作用独立于血压升高和雄激素水平。
