Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice
Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice
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DOI：
10.1096/fj.10-160119
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Zeldin, Darryl C.
中科院分区：
文献类型：
--
作者：
Lee, Craig R.;Imig, John D.;Zeldin, Darryl C.
肾细胞色素P450（CYP）衍生的环氧二十碳三烯酸（E3）调节钠转运和血压。虽然内皮细胞CYP衍生的内皮素是有效的血管扩张剂，但其对血压调节的作用尚不清楚。因此，我们开发了具有人CYP 2 J2和CYP 2C 8环氧合酶的内皮表达的转基因小鼠，以增加内皮EET生物合成。与野生型同窝对照相比，在CYP 2 J2和CYP 2C 8转基因小鼠中观察到对内皮素-1的传入小动脉收缩反应减弱，对乙酰胆碱的扩张反应增强。与野生型对照组相比，CYP 2 J2和CYP 2C 8转基因小鼠在基础条件下表现出适度但不显著的平均动脉压降低。然而，在N-硝基-L-精氨酸甲酯和吲哚美辛联合给药期间，CYP 2 J2和CYP 2C 8转基因小鼠的平均动脉压显著降低。在一个单独的实验中，高盐饮食和皮下血管紧张素II超过4周。与野生型对照组相比，CYP 2 J2和CYP 2C 8转基因小鼠中血管紧张素/高盐诱导的收缩压升高、蛋白尿和肾小球损伤显著减弱。总的来说，这些数据表明，增加内皮细胞环氧合酶的表达减弱传入小动脉收缩反应性和高血压诱导的小鼠血压和肾损伤的增加。我们的结论是，内皮细胞环氧合酶的功能有助于血压的调节。李角，澳-地R.，Imig，J.D.，Edin，M. E、Foley，J.，德格拉夫湖M.，布拉德伯里，J. A.，格雷夫斯，J. P.，Lih，F. B.，克拉克，J.，迈尔斯，P.，Perrow，A. L.，Lepp，A. N.，Kannon，M.一、龙内克莱夫岛K.，Alkayed，N. J.，法尔克，J. R.，Tomer，K. B.，Zeldin，D. C.人细胞色素P450表氧合酶在内皮细胞的表达可降低血压并减轻高血压诱导的小鼠肾损伤FASEB J.24，3770-3781（2010）。www.fasebj.org
Renal cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) regulate sodium transport and blood pressure. Although endothelial CYP-derived EETs are potent vasodilators, their contribution to the regulation of blood pressure remains unclear. Consequently, we developed transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases to increase endothelial EET biosynthesis. Compared to wild-type littermate controls, an attenuated afferent arteriole constrictor response to endothelin-1 and enhanced dilator response to acetylcholine was observed in CYP2J2 and CYP2C8 transgenic mice. CYP2J2 and CYP2C8 transgenic mice demonstrated modestly, but not significantly, lower mean arterial pressure under basal conditions compared to wild-type controls. However, mean arterial pressure was significantly lower in both CYP2J2 and CYP2C8 transgenic mice during coadministration of N-nitro-L-arginine methyl ester and indomethacin. In a separate experiment, a high-salt diet and subcutaneous angiotensin II was administered over 4 wk. The angiotensin/high-saltinduced increase in systolic blood pressure, proteinuria, and glomerular injury was significantly attenuated in CYP2J2 and CYP2C8 transgenic mice compared to wild-type controls. Collectively, these data demonstrate that increased endothelial CYP epoxygenase expression attenuates afferent arteriolar constrictor reactivity and hypertension-induced increases in blood pressure and renal injury in mice. We conclude that endothelial CYP epoxygenase function contributes to the regulation of blood pressure.-Lee, C. R., Imig, J. D., Edin, M. E., Foley, J., DeGraff, L. M., Bradbury, J. A., Graves, J. P., Lih, F. B., Clark, J., Myers, P., Perrow, A. L., Lepp, A. N., Kannon, M. A., Ronnekleiv, O. K., Alkayed, N. J., Falck, J. R., Tomer, K. B., Zeldin, D. C. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB J. 24, 3770-3781 (2010). www.fasebj.org