Montreal Heart Institute, Research Center, Montreal, Quebec, Canada; Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; and.
Montreal Heart Institute, Research Center, Montreal, Quebec, Canada;
Am J Physiol Heart Circ Physiol. 2015 Mar 1;308(5):H386-97. doi: 10.1152/ajpheart.00278.2014. Epub 2014 Dec 19.
Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng·kg(-1)·min(-1), n = 15) or saline (n = 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O2 (-)/H2O2 contributed to dilation in WT mice, eNOS-derived NO (P < 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice (P < 0.05), which was reversed (P < 0.05) by either N-acetyl-l-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactive oxygen species from Nox2 and Cox-derived contractile factors. In KD mice treated with ANG II, endothelial function was preserved, likely via Nox-derived H2O2, sensitive to apocynin and PEG-catalase (P < 0.05), but not to gp91ds-tat. In the aorta, relaxation similarly and essentially depended on NO; endothelial function was maintained after ANG II infusion in all groups, but apocynin significantly reduced aortic relaxation in KD mice (P < 0.05). Protein expression levels of Nox1/2 in cerebral arteries were similar among all groups, but that of Nox4 was greater (P < 0.05) in saline-treated KD mice. In conclusion, knockdown of angptl2 may be protective against ANG II-induced cerebral endothelial dysfunction; it favors the production of NO, likely increasing endothelial cell resistance to stress, and permits the expression of an alternative vasodilatory Nox pathway.
血管生成素样蛋白 2（angptl2）是一种循环的促炎和促氧化蛋白，但它在调节脑内皮功能中的作用尚不清楚。我们假设，在 angptl2 敲低（KD）的小鼠中，脑内皮功能将免受 ANG II 诱导的损伤。将 ANG II（200ng·kg（-1）·min（-1），n=15）或盐水（n=15）皮下输注到 20 周龄 angptl2 KD 小鼠和野生型（WT）同窝仔鼠中 14 天。在盐水处理的 KD 和 WT 小鼠中，分离的脑动脉乙酰胆碱诱导扩张的幅度和敏感性相似。然而，虽然内皮型一氧化氮合酶（eNOS）衍生的 O2（-）/H2O2 有助于 WT 小鼠的扩张，但 eNOS 衍生的 NO 参与了 KD 小鼠的扩张（P<0.05）。ANG II 仅在 WT 小鼠中诱导脑内皮功能障碍（P<0.05），这一现象被 N-乙酰-L-半胱氨酸、apocynin、gp91ds-tat 或吲哚美辛逆转（P<0.05），提示 Nox2 和 Cox 衍生的收缩因子产生的活性氧的贡献。在接受 ANG II 治疗的 KD 小鼠中，内皮功能得到了保护，这可能是通过 Nox 衍生的 H2O2 介导的，对 apocynin 和 PEG-过氧化氢酶敏感（P<0.05），但对 gp91ds-tat 不敏感。在主动脉中，松弛同样且基本上依赖于 NO；在所有组中，内皮功能在 ANG II 输注后均得到维持，但 apocynin 显著降低 KD 小鼠的主动脉松弛（P<0.05）。脑动脉中 Nox1/2 的蛋白表达水平在所有组中相似，但在盐水处理的 KD 小鼠中 Nox4 的表达更高（P<0.05）。总之，angptl2 的敲低可能对 ANG II 诱导的脑内皮功能障碍具有保护作用；它有利于 NO 的产生，可能增加内皮细胞对应激的抵抗力，并允许表达替代的血管舒张 Nox 途径。
