The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
J Pharmacol Exp Ther. 2010 Sep 1;334(3):784-94. doi: 10.1124/jpet.110.167510. Epub 2010 May 25.
Cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) exert well recognized vasodilatory, diuretic, and tubular fluid-electrolyte transport actions that are predictive of a hypotensive effect. The study sought to determine the improvement of hypertension and cardiac function by overexpressing P450 epoxygenases in vivo. Long-term expression of CYP102 F87V or CYP2J2 in spontaneously hypertensive rats (SHR) was mediated by using a type 8 recombinant adeno-associated virus (rAAV8) vector. Hemodynamics was measured by a Millar Instruments, Inc. (Houston, TX) microtransducer catheter, and atrial natriuretic peptide (ANP) mRNA levels were tested by real-time polymerase chain reaction. Results showed that urinary excretion of 14,15-EET was increased at 2 and 6 months after injection with rAAV-CYP102 F87V and rAAV-CYP2J2 compared with controls (p < 0.05). During the course of the 6-month study, systolic blood pressure significantly decreased in P450 epoxygenase-treated rats, but the CYP2J2-specific inhibitor C26 blocked rAAV-CYP2J2-induced hypotension and the increase in EET production. Cardiac output was improved by P450 epoxygenase expression at 6 months (p < 0.05). Furthermore, cardiac collagen content was reduced in P450 epoxygenase-treated rats. ANP mRNA levels were up-regulated 6- to 14-fold in the myocardium, and ANP expression was significantly increased in both myocardium and plasma in P450 epoxygenase-treated rats. However, epidermal growth factor (EGF) receptor antagonist 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG-1478) significantly attenuated the increase in the EET-induced expression of ANP in vitro. These data indicate that overexpression of P450 epoxygenases attenuates the development of hypertension and improves cardiac function in SHR, and that these effects may be mediated, at least in part, by ANP via activating EGF receptor.
细胞色素 P450（P450）衍生的环氧二十碳三烯酸（EETs）具有公认的血管扩张、利尿和管状液电解质转运作用，可预测降压作用。本研究旨在通过在体内过表达 P450 加氧酶来确定高血压和心脏功能的改善。通过使用 8 型重组腺相关病毒（rAAV8）载体，长期表达 CYP102 F87V 或 CYP2J2 在自发性高血压大鼠（SHR）中得到介导。通过 Millar Instruments，Inc.（休斯顿，TX）微传感器导管测量血流动力学，通过实时聚合酶链反应测试心房利钠肽（ANP）mRNA 水平。结果表明，与对照组相比，注射 rAAV-CYP102 F87V 和 rAAV-CYP2J2 后 2 个月和 6 个月，14,15-EET 的尿排泄量增加（p<0.05）。在 6 个月的研究过程中，P450 加氧酶治疗组的收缩压显著降低，但 CYP2J2 特异性抑制剂 C26 阻断了 rAAV-CYP2J2 诱导的低血压和 EET 产生的增加。6 个月时 P450 加氧酶表达改善了心输出量（p<0.05）。此外，P450 加氧酶治疗组的心肌胶原含量降低。心肌中 ANP mRNA 水平上调 6 至 14 倍，P450 加氧酶治疗组心肌和血浆中 ANP 表达均显著增加。然而，表皮生长因子（EGF）受体拮抗剂 4-（3'-氯苯胺基）-6,7-二甲氧基喹唑啉（AG-1478）显著减弱了 EET 诱导的 ANP 表达的增加。这些数据表明，过表达 P450 加氧酶可减轻 SHR 高血压的发展并改善心脏功能，这些作用至少部分通过激活 EGF 受体介导的 ANP 来实现。
