Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice
Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice
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DOI：
10.1177/1074248412460124
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发表时间：
2013-03-01
影响因子：
2.6
通讯作者：
Morris, Mariana
中科院分区：
文献类型：
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作者：
Alghamri, Mahmoud S.;Weir, Nathan M.;Morris, Mariana
血管紧张素转换酶2 （ACE2）存在于心脏中，被认为具有保护功能。我们在ACE2缺陷小鼠中进行了研究，以确定酶丢失是否会加剧慢性皮下（sc）血管紧张素II （Ang II）输注的心脏和血管病理反应。8周龄雄性ACE2敲除小鼠（KO）和野生型小鼠（WT）采用微渗透泵灌注Ang II （1000 ng/kg / min， 4周）。检查血压（无线电遥测）、心功能（超声心动图、回声）、心脏/主动脉结构（组织学、胶原蛋白和氧化应激）和血管炎症。在注入angii之前，ACE2 KO小鼠的心功能和血压没有改变。注射angii 4周后，WT组的平均动脉压（MAP）从96 +/- 2增加到136 +/- 17 mm Hg (40%)， ACE2组的平均动脉压（MAP）从104 +/- 5增加到141 +/- 13 mm Hg（35%）。虽然MAP在两组间无差异，但ACE2 KO对高血压刺激的反应不同。回声分析显示，angii输注的ACE2 KO （angace2 KO）心肌功能严重。在ACE2 KO和WT中，射血分数分别较低（39%比50%）和分数缩短（27%比38%）。心功能障碍与肥厚性心肌病相关，表现为左心室壁厚度、平均心肌细胞横截面积和心脏重量/体重比增加。心肌和主动脉胶原染色显示Ang ACE2 KO胶原增加，提示重构。结果还显示angace2 KO心肌和主动脉氧化应激增强。ACE2 KO患者主动脉巨噬细胞炎性蛋白1 α (MIP 1 α)升高3倍。ACE2 KO模型的研究揭示了ACE2在心脏和主动脉对Ang II刺激的不适应反应中的重要性，这被认为是生理、结构和生化标志物增强的重塑。结果证明ACE2在病理条件下具有心脏和血管保护作用。
Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 +/- 2 to 136 +/- 17 mm Hg ( 40%) in WT and from 104 +/- 5 to 141 +/- 13 mm Hg ( 35%) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39% versus 50%) as was fractional shortening (27% versus 38%) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1 alpha (MIP 1 alpha) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular-protective role of ACE2 under pathological conditions.