Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat
Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat
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DOI：
10.1152/ajpheart.00953.2007
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Dellsperger, Kevin C.
中科院分区：
文献类型：
--
作者：
DeMarco, Vincent G.;Habibi, Javad;Dellsperger, Kevin C.
转基因（mRen 2）27（Ren 2）大鼠在肾外组织中过度表达小鼠肾素，导致ANG II的局部合成增加、氧化应激和高血压。然而，很少有人知道的作用，氧化应激诱导的组织肾素-血管紧张素系统（RAS）作为一个促成因素，在肺动脉高压（PH）。使用雄性Ren 2大鼠，我们测试肺组织RAS过度表达和由此产生的氧化应激有助于PH和肺血管重构的假设。比较了年龄匹配的Ren 2和Sprague-Dawley（SD）大鼠经SOD/过氧化氢酶模拟物tempol预处理21天后的平均动脉压（MAP）、右心室收缩压（RVSP）、肺小动脉壁厚度（PA）以及肺内NADPH氧化酶活性、亚单位蛋白表达和活性氧（ROS）。与安慰剂组相比，安慰剂组Ren 2大鼠MAP、RVSP、肺内NADPH氧化酶活性及亚单位（Nox 2、p22（phox）和Rac-1）和ROS均升高（P < 0.05）。Tempol可降低Ren 2大鼠RVSP（P < 0.05），但对MAP无影响。Tempol还可降低Ren 2大鼠肺内NADPH氧化酶活性、Nox 2、p22 phox和Rac-1蛋白表达及ROS水平（P < 0.05）。与SD大鼠相比，Ren 2大鼠小PA的横截面积增加38%（P < 0.001），管腔面积减少54%（P < 0.001）。与对照组相比，tempo处理组SD和Ren 2大鼠的管壁表面积减少，管腔面积增加（P < 0.05）。总的来说，本研究的结果支持增强的组织RAS/氧化应激作为PH和肺血管重塑发展的因素的开创性作用。
The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22(phox), and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P < 0.05). Tempol decreased RVSP (P < 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22phox, and Rac-1 protein expression, and ROS in Ren2 rats (P < 0.05). Compared with SD rats, the cross-sectional surface area of small PA was 38% greater (P < 0.001) and luminal surface area was 54% less (P < 0.001) in Ren2 rats. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with untreated controls (P < 0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling.