Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: The possible role of local renin-angiotensin system
Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: The possible role of local renin-angiotensin system
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DOI：
10.1210/en.2006-1157
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发表时间：
2007-04-01
期刊：
影响因子：
4.8
通讯作者：
Hirata, Yukio
中科院分区：
文献类型：
--
作者：
Hirono, Yuki;Yoshimoto, Takanobu;Hirata, Yukio
最近，醛固酮已被证明激活局部肾素-血管紧张素系统在体外。为了阐明局部肾素-血管紧张素系统在醛固酮诱导的心血管损伤中的潜在作用，我们研究了选择性盐皮质激素受体（MR）拮抗剂依普利酮（EPL）、血管紧张素（Ang）II 1型受体拮抗剂坎地沙坦（ARB）和超氧化物歧化酶模拟物tempol（TEM）对高血压、血管损伤、氧化应激醛固酮治疗高血压大鼠炎症相关基因的表达。与EPL、ARB或TEM联合治疗可减弱收缩压升高和血管炎症变化。醛固酮增加血管紧张素转换酶在主动脉组织中的表达，其作用被EPL阻断，而不是ARB或TEM。醛固酮也增加血管紧张素II含量在主动脉组织中的存在下，低循环血管紧张素II浓度。醛固酮诱导各种炎症相关基因的表达，其影响被取消的EPL，而ARB和TEM的抑制作用根据基因而异。醛固酮引起氧化应激标记物4-羟基-2-藜芦烯醛在内皮细胞中的更大积累;其作用被EPL、ARB或TEM消除。醛固酮增加减少烟酰胺腺嘌呤二核苷酸磷酸氧化酶组分的mRNA水平，其效果被废除的EPL，而ARB和TEM只降低p47 phox的mRNA水平，但不是p22 phox或gp 91 phox。目前的研究结果表明，血管紧张素转换酶上调引起的血管紧张素II依赖性途径和血管紧张素II非依赖性途径都参与了导致高血压，血管炎症和醛固酮诱导的氧化应激的发展的潜在机制。
Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.