Garcia Victor, Joseph Gregory, Shkolnik Brian, Ding Yan, Zhang Frank Fan, Gotlinger Katherine, Falck John R, Dakarapu Rambabu, Capdevila Jorge H, Bernstein Kenneth E, Schwartzman Michal Laniado
Department of Pharmacology, New York Medical College, Valhalla, New York;
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas;
Am J Physiol Regul Integr Comp Physiol. 2015 Jul 1;309(1):R71-8. doi: 10.1152/ajpregu.00039.2015. Epub 2015 Apr 29.
Increased vascular 20-HETE is associated with hypertension and activation of the renin-angiotensin system (RAS) through induction of vascular angiotensin-converting enzyme (ACE) expression. Cyp4a12tg mice, whose Cyp4a12-20-HETE synthase expression is under the control of a tetracycline (doxycycline, DOX) promoter, were used to assess the contribution of ACE/RAS to microvascular remodeling in 20-HETE-dependent hypertension. Treatment of Cyp4a12tg mice with DOX increased systolic blood pressure (SBP; 136 ± 2 vs. 102 ± 1 mmHg; P < 0.05), and this increase was prevented by administration of 20-HEDGE, lisinopril, or losartan. DOX-induced hypertension was associated with microvascular dysfunction and remodeling of preglomerular microvessels, which was prevented by 20-HEDGE, a 20-HETE antagonist, yet only lessened, but not prevented, by lisinopril or losartan. In ACE 3/3 mice, which lack vascular endothelial ACE, administration of 5α-dihydrotestosterone (DHT), a known inducer of 20-HETE production, increased SBP; however, the increase was about 50% of that in wild-type (WT) mice (151 ± 1 vs. 126 ± 1 mmHg). Losartan and 20-HEDGE prevented the DHT-induced increase in SBP in WT and ACE 3/3 mice. DHT treatment increased 20-HETE production and microvascular remodeling in WT and ACE 3/3 mice; however, remodeling was attenuated in the ACE 3/3 mice as opposed to WT mice (15.83 ± 1.11 vs. 22.17 ± 0.92 μm; P < 0.05). 20-HEDGE prevented microvascular remodeling in WT and ACE 3/3 mice, while losartan had no effect on microvascular remodeling in ACE 3/3. Taken together, these results suggest that RAS contributes to 20-HETE-mediated microvascular remodeling in hypertension and that 20-HETE-driven microvascular remodeling independent of blood pressure elevation does not fully rely on ACE activity in the vascular endothelium.
血管20-羟基二十碳四烯酸（20-HETE）水平升高与高血压以及肾素-血管紧张素系统（RAS）激活相关，其机制是通过诱导血管紧张素转换酶（ACE）表达实现的。利用Cyp4a12tg小鼠（其Cyp4a12 - 20-HETE合酶表达受四环素（强力霉素，DOX）启动子控制）来评估ACE/RAS在20-HETE依赖性高血压中对微血管重塑的作用。用DOX处理Cyp4a12tg小鼠会使收缩压（SBP）升高（136±2 vs. 102±1 mmHg；P<0.05），而给予20-HEDGE、赖诺普利或氯沙坦可预防这种升高。DOX诱导的高血压与微血管功能障碍以及球前微血管重塑相关，20-HETE拮抗剂20-HEDGE可预防这种情况，而赖诺普利或氯沙坦仅能减轻但不能预防。在缺乏血管内皮ACE的ACE 3/3小鼠中，给予已知的20-HETE生成诱导剂5α-二氢睾酮（DHT）会使SBP升高；然而，升高幅度约为野生型（WT）小鼠的50%（151±1 vs. 126±1 mmHg）。氯沙坦和20-HEDGE可预防WT和ACE 3/3小鼠中DHT诱导的SBP升高。DHT处理会增加WT和ACE 3/3小鼠的20-HETE生成以及微血管重塑；然而，与WT小鼠相比，ACE 3/3小鼠中的重塑减弱（15.83±1.11 vs. 22.17±0.92μm；P<0.05）。20-HEDGE可预防WT和ACE 3/3小鼠的微血管重塑，而氯沙坦对ACE 3/3小鼠的微血管重塑无影响。综上所述，这些结果表明RAS在高血压中促成了20-HETE介导的微血管重塑，并且20-HETE驱动的不依赖血压升高的微血管重塑并不完全依赖于血管内皮中的ACE活性。
