Whaley-Connell Adam, Habibi Javad, Cooper Shawna A, Demarco Vincent G, Hayden Melvin R, Stump Craig S, Link Daniel, Ferrario Carlos M, Sowers James R
The University of Missouri School of Medicine, Department of Medicine, Columbia, Missouri, USA.
Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E103-9. doi: 10.1152/ajpendo.00752.2007. Epub 2008 May 6.
Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT(1)R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT(1)R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/-) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT(1)R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT(1)R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.
血管紧张素 II（Ang II）刺激血管紧张素 1 型受体（AT(1)R），通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶介导的氧化应激生成促进心肌重塑。肾素 - 血管紧张素系统的组成部分在心肌中构成一个自分泌/旁分泌单位，包括肾素，它是 Ang II 生成中的限速步骤。本研究旨在确定在慢性组织 Ang II 水平升高的啮齿动物模型——转基因（mRen2）27 大鼠（Ren2）中，体内肾素抑制和/或 AT(1)R 阻断是否能减轻心脏氧化应激和细胞重塑。Ren2 大鼠过度表达小鼠肾素转基因，导致高血压、胰岛素抵抗和心血管损伤。对年轻（6 至 7 周龄）的杂合子（+/-）雄性 Ren2 大鼠和年龄匹配的斯普拉格 - 道利大鼠，用对人和小鼠肾素具有高优先亲和力的肾素抑制剂阿利吉仑、AT(1)R 阻滞剂厄贝沙坦或安慰剂治疗 3 周。评估心肌 NADPH 氧化酶活性以及对 NADPH 氧化酶亚基和 3 - 硝基酪氨酸进行免疫染色，并通过光学显微镜和透射电子显微镜评估重塑变化。与同窝的斯普拉格 - 道利大鼠相比，Ren2 大鼠的血压、心肌 NADPH 氧化酶活性和亚基免疫染色、3 - 硝基酪氨酸、血管周围纤维化、线粒体含量及活性标志物均显著增加。肾素抑制和 AT(1)R 阻断均显著减轻了心脏功能和结构改变，尽管厄贝沙坦治疗导致血压和氧化应激标志物的降低幅度更大。总体而言，这些数据表明二者均能减轻部分由 Ang II 介导的 NADPH 氧化酶增加以及部分由血压升高所驱动的变化。
