D5 dopamine receptor decreases NADPH oxidase, reactive oxygen species and blood pressure via heme oxygenase-1.
D5 dopamine receptor decreases NADPH oxidase, reactive oxygen species and blood pressure via heme oxygenase-1.
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D5多巴胺受体通过血红素加氧酶-1降低NADPH氧化酶，活性氧和血压。
DOI：
10.1038/hr.2013.9
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发表时间：
2013-08
影响因子：
5.4
通讯作者：
Jose, Pedro A.
中科院分区：
文献类型：
--
作者：
Lu, Quansheng;Yang, Yu;Villar, Van Anthony;Asico, Laureano;Jones, John E.;Yu, Peiying;Li, Hewang;Weinman, Edward J.;Eisner, Gilbert M.;Jose, Pedro A.
D5多巴胺受体(D5R)基因敲除小鼠(D5−/−)比其D5R野生型窝鼠(D5+/+)具有更高的血压(BP)和更高的活性氧(ROS)产生。我们验证了D5−/−小鼠血压升高和ROS产生增加可能是由于血红素加氧酶-1(HO-1)表达和活性降低所致。我们发现，与D5+/+小鼠相比，D5−/−小鼠肾脏HO-1蛋白表达和HO酶活性分别降低了65%和50%。给予HO-1诱导剂氯化血红素可使D5−/−小鼠HO-1表达和HO活性增加(分别为6.8倍和1.9倍)，并使增加的ROS产生和血压正常化。异源表达人野生型D5R(HEK-hD5R)的HEK细胞HO-1蛋白表达和HO活性分别增加2.3倍和1.5倍，而空载体转染组HEK-293细胞HO-1蛋白表达和HO活性无明显变化。D5R激动剂非诺多巴(Fen)可增加HEK-hD5R细胞HO活性(3h)、HO-1蛋白表达、HO-1与D5R共定位和免疫共沉淀。血红素加氧酶1基因(Hmox1)沉默后，HEK-hD5R细胞的NADPH氧化酶活性下降了35%。Hmox1 siRNA也削弱了Fen降低HEK-hD5R细胞NADPH氧化酶活性的能力。综上所述，D5R在短期内通过直接的蛋白质/蛋白质相互作用和在长期通过增加HO-1蛋白的表达来积极调节HO-1。D5R对HO-1和ROS产生的调节受损参与了D5−/−小鼠高血压的发病机制。
D5 dopamine receptor (D5R) knock-out mice (D5−/−) have a higher blood pressure (BP) and higher reactive oxygen species (ROS) production than their D5R wild-type littermates (D5+/+). We tested the hypothesis that the high BP and increased ROS production in D5−/− mice may be caused by decreased heme oxygenase-1 (HO-1) expression and activity. We found that renal HO-1 protein expression and HO enzyme activity were decreased (65 and 50%, respectively) in D5−/− relative to D5+/+ mice. A 24 h of administration of hemin, an HO-1 inducer, increased HO-1 expression and HO activity (6.8- and 1.9-fold, respectively) and normalized the increased ROS production and BP in D5−/− mice. Expression of HO-1 protein and HO activity were increased (2.3- and 1.5-fold, respectively) in HEK cells that heterologously expressed human wild-type D5R (HEK-hD5R), but not the empty vector-transfected HEK-293 cells. Fenoldopam (Fen), a D5R agonist, increased HO activity (3 h), HO-1 protein expression, HO-1 and D5R colocalization and co-immunoprecipitation in HEK-hD5R cells. Cellular NADPH oxidase activity was decreased by 35% in HEK-hD5R that was abrogated with silencing of the heme oxygenase 1 gene (HMOX1). HMOX1 siRNA also impaired the ability of Fen to decrease NADPH oxidase activity in HEK-hD5R cells. In summary, the D5R positively regulates HO-1 through direct protein/protein interaction in the short-term and by increasing HO-1 protein expression in the long-term. The impaired D5R regulation of HO-1 and ROS production contributes to the pathogenesis of hypertension in D5−/− mice.
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影响因子：
5.6
作者：
Briones, Ana M.;Touyz, Rhian M.
通讯作者：
Touyz, Rhian M.
影响因子：
8.3
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Ortiz, PA;Garvin, JL
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Bek, MJ;Wang, XY;Jose, PA
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Cooper, RS;Luke, A;Ward, R
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Ward, R
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8.3
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Li, XX;Bek, M;Jose, PA
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