Department of Cardiovascular Medicine, University of Missouri, Columbia, MO, USA.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
J Cell Mol Med. 2020 Jul;24(13):7393-7404. doi: 10.1111/jcmm.15342. Epub 2020 May 18.
Clinical and experimental studies show that angiotensin II (AngII) promotes vascular pathology via activation of AngII type 1 receptors (AT1Rs). We recently reported that NP-6A4, a selective peptide agonist for AngII type 2 receptor (AT2R), exerts protective effects on human vascular cells subjected to serum starvation or doxorubicin exposure. In this study, we investigated whether NP-6A4-induced AT2R activation could mitigate AngII-induced abdominal aortic aneurism (AAA) using AngII-treated Apoe mice. Male Apoe mice were infused with AngII (1 µg/kg/min) by implanting osmotic pumps subcutaneously for 28 days. A subset of mice was pre-treated subcutaneously with NP-6A4 (2.5 mg/kg/day) or vehicle for 14 days prior to AngII, and treatments were continued for 28 days. NP-6A4 significantly reduced aortic stiffness of the abdominal aorta induced by AngII as determined by ultrasound functional analyses and histochemical analyses. NP-6A4 also increased nitric oxide bioavailability in aortic tissues and suppressed AngII-induced increases in monocyte chemotactic protein-1, osteopontin and proteolytic activity of the aorta. However, NP-6A4 did not affect maximal intraluminal aortic diameter or AAA incidences significantly. These data suggest that the effects of AT2R agonist on vascular pathologies are selective, affecting the aortic stiffness and proteolytic activity without affecting the size of AAA.
临床和实验研究表明，血管紧张素 II（AngII）通过激活 AngII 型 1 受体（AT1R）促进血管病理学。我们最近报道，NP-6A4 是 AngII 型 2 受体（AT2R）的选择性肽激动剂，对血清饥饿或阿霉素暴露的人血管细胞具有保护作用。在这项研究中，我们研究了 NP-6A4 诱导的 AT2R 激活是否可以减轻 AngII 诱导的腹主动脉瘤（AAA），使用 AngII 处理的 Apoe 小鼠。雄性 Apoe 小鼠通过皮下植入渗透泵以 1μg/kg/min 的速度输注 AngII 28 天。一部分小鼠在 AngII 之前预先皮下给予 NP-6A4（2.5mg/kg/天）或载体 14 天，并且治疗持续 28 天。超声功能分析和组织化学分析表明，NP-6A4 显著降低了 AngII 诱导的腹主动脉的主动脉僵硬。NP-6A4 还增加了主动脉组织中一氧化氮的生物利用度，并抑制了 AngII 诱导的单核细胞趋化蛋白-1、骨桥蛋白和主动脉蛋白水解活性的增加。然而，NP-6A4 对最大腔内主动脉直径或 AAA 发生率没有显著影响。这些数据表明，AT2R 激动剂对血管病理学的影响是选择性的，影响主动脉僵硬和蛋白水解活性，而不影响 AAA 的大小。
