Erythropoietin attenuated vascular dysfunction and inflammation by inhibiting NADPH oxidase-derived superoxide production in nitric oxide synthase-inhibited hypertensive rat aorta
Erythropoietin attenuated vascular dysfunction and inflammation by inhibiting NADPH oxidase-derived superoxide production in nitric oxide synthase-inhibited hypertensive rat aorta
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DOI：
10.1016/j.ejphar.2012.07.018
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发表时间：
2012-09-15
影响因子：
5
通讯作者：
Nakata, Tetsuo
中科院分区：
文献类型：
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作者：
Toba, Hiroe;Kojima, Yushi;Nakata, Tetsuo
促红细胞生成素（EPO），临床上用于肾性贫血，据报道在各种组织中发挥有益的多效性作用。最近的研究表明，一氧化氮（NO）在EPO诱导的组织保护中起重要作用。本研究探讨重组人促红细胞生成素（rHuEPO）是否具有血管保护作用，即使在NO还原酶抑制状态。在饮用水（0.7mg/ml）中接受NO合酶抑制剂N-G-硝基-L-精氨酸甲酯（L-NAME）的大鼠用rHuEPO（75 U/kg，s.c.）一周三次，持续两周。对L-NAME处理的大鼠给予rHuEPO对红细胞压积值或血压升高没有影响。血管舒张反应乙酰胆碱在主动脉环受损的L-NAME治疗的大鼠，并改善rHuEPO。免疫组织化学染色显示，巨噬细胞的浸润和骨桥蛋白的表达增强，L-NAME治疗的大鼠主动脉，和过度表达的抑制由rHuEPO。rHuEPO也能减轻中膜增生。Akt信号的激活在rHuEPO处理的大鼠中是明显的，因为磷酸化Akt的表达增加。rHuEPO增强主动脉中抗氧化酶如Cu/Zn-超氧化物歧化酶和血红素加氧酶-1的表达。此外，rHuEPO减少NADPH氧化酶依赖性超氧化物的产生，并增强细胞因子信号转导抑制因子-1（SOCS-1）在L-NAME处理的大鼠主动脉中的表达。这些结果表明，即使在药理学NO合酶抑制状态下，低剂量的rHuEPO也会导致内皮功能和血管炎症正常化，而不仅仅是造血。这些作用可能是由于rHuEPO的抗氧化特性。SOCS-1过表达可能在抑制NADPH氧化酶活性方面起重要作用。(C)2012爱思唯尔有限公司版权所有。
Erythropoietin (EPO), used clinically for renal anemia, reportedly exerts beneficial pleiotropic effects in various tissues. Recent studies suggest that nitric oxide (NO) plays an important role in EPO-induced tissue protection. The present study investigated whether recombinant human EPO (rHuEPO) exhibits vasoprotective effects even in the NO synthase-inhibited state. Rats that received a NO synthase inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME), in drinking water (0.7 mg/ml) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. The administration of rHuEPO to L-NAME-treated rats had no effect on hematocrit values or increased blood pressure. Vasodilation in response to acetylcholine in the aortic ring was impaired in the L-NAME-treated rats, and improved by rHuEPO. Immunohistochemical staining revealed that infiltration by macrophages and expression of osteopontin were enhanced in the L-NAME-treated rat aorta, and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Activation of Akt signaling was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt. rHuEPO enhanced the expression of antioxidant enzymes such as Cu/Zn-superoxide dismutase and heme oxygenase-1 in the aorta. In addition, rHuEPO reduced NADPH oxidase-dependent superoxide production and enhanced the expression of suppressor of cytokine signaling-1(SOCS-1) in the L-NAME-treated rat aorta. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function and vascular inflammation beyond hematopoiesis even in a pharmacologically NO synthase-inhibited state. These effects might be due to the antioxidant properties of rHuEPO. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation. (C) 2012 Elsevier B.V. All rights reserved.