Adrenomedullin and angiotensin II signaling pathways involved in the effects on cerebellar antioxidant enzymes activity
Adrenomedullin and angiotensin II signaling pathways involved in the effects on cerebellar antioxidant enzymes activity
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DOI：
10.1016/j.brainresbull.2016.11.012
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发表时间：
2017-01-01
影响因子：
3.8
通讯作者：
Anita, Israel
中科院分区：
文献类型：
--
作者：
Leticia, Figueira;Anita, Israel
人肾上腺髓质素（AM）是一种由52个氨基酸组成的多肽，参与心血管控制。AM具有由降钙素受体样受体（CRLR）和受体活性修饰蛋白（RAMP）2或3形成的两种特异性受体，分别称为AM 1和AM 2受体。此外，AM对由CRLR/RAMP 1组成的降钙素基因-1相关肽受体（CGRP 1）具有明显的亲和力。在脑中，AM及其受体在包括小脑在内的几个局部区域表达。AM已被报道为抗氧化剂。AM在小脑活性氧代谢中的作用目前尚不清楚。我们评估了AM对三种抗氧化酶活性的影响：过氧化氢酶（CAT），谷胱甘肽过氧化物酶（GPx）和超氧化物歧化酶（SOD）和硫代巴比妥酸反应物质（TSARS）在大鼠小脑蚓部的生产，以及参与AM行动的受体亚型。此外，我们还评估了血管紧张素II（ANG II）、蛋白激酶A（PICA）活性和蛋白激酶C/烟酰胺腺嘌呤二核苷酸磷酸氧化酶（PKC/NAD（P）H）（氧化酶）途径的作用。通过断头处死Sprague-Dawley大鼠，并在立体显微镜控制下显微解剖小脑蚓部。采用比色法测定CAT、GPx、SOD活性和TBARS产生量。我们的研究结果表明，在小脑蚓部，AM减少和ANG II增加CAT，GPx和SOD活性和TBARS的生产。同样，AM拮抗ANG II诱导的抗氧化酶活性的增加。AM（22-50）和CGRP（8-37）减弱了AM诱导的抗氧化酶活性和TBARS产生的降低，表明这些作用是通过AM和CGRP 1受体介导的。此外，PICA抑制剂（PKAi）钝化AM的行动和夹竹桃苷和白屈菜红碱逆转ANG II的行动，这表明AM的抗氧化作用是通过刺激PICA活性介导的，而ANG II诱导的刺激通过PKC/NAD（P）H氧化酶途径。我们的研究结果支持AM在小脑抗氧化酶活性的调节中的作用，并表明AM在小脑中的生理作用。(C)2016 Elsevier Inc. All rights reserved.
Human adrenomedullin (AM) is a 52-amino acid peptide involved in cardiovascular control. AM has two specific receptors formed by the calcitonin-receptor-like receptor (CRLR) and receptor activity-modifying protein (RAMP) 2 or 3, known as AM1 and AM2 receptors, respectively. In addition, AM has appreciable affinity for the calcitonin gene-1 related peptide receptor (CGRP1), composed of CRLR/RAMP1. In brain, AM and their receptors are expressed in several localized areas, including the cerebellum. AM has been reported as an antioxidant. Little is known about the role of AM in the regulation of cerebellar reactive oxygen species (ROS) metabolism. We assessed the effect of AM on three antioxidant enzymes activity: catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) and on thiobarbituric acid reactive substances (TSARS) production in rat cerebellar vermis, as well the receptor subtypes involved in AM actions. Additionally, we evaluated the role of angiotensin II (ANG II), protein kinase A (PICA) activity, and protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase (PKC/NAD(P)H) (oxidase) pathway. Sprague-Dawley rats were sacrificed by decapitation and cerebellar vermis was microdissected under stereomicroscopic control. CAT, GPx, SOD activity and TBARS production was determined spectrophotometrically. Our findings demonstrated that in cerebellar vermis, AM decreased and ANG II increased CAT, GPx and SOD activity and TBARS production. Likewise, AM antagonized ANG II-induced increase antioxidant enzyme activity. AM(22-50) and CGRP(8-37) blunted AM-induced decrease of antioxidant enzymes activity and TBARS production indicating that these actions are mediated through AM and CGRP1 receptors. Further, PICA inhibitor (PKAi) blunted AM action and apocynin and chelerythrine reverted ANG II action, suggesting that AM antioxidant action is mediated through stimulation of PICA activity, while ANG II-induced stimulation through PKC/NAD(P)H oxidase pathway. Our results support the role of AM in the regulation of cerebellar antioxidant enzymes activity and suggest a physiological role for AM in cerebellum. (C) 2016 Elsevier Inc. All rights reserved.