INTRODUCTION:In the present study, we aimed to explore the functional role of Pellino-1 (Peli1) in inducing neovascularization after myocardial infarction (MI) and hindlimb ischemia (HLI) using Peli1 global knockout mice (Peli1-/-). Recently we have shown that Peli1, an E3 ubiquitin ligase, induce angiogenesis and improve survivability, with decreased necrosis of ischemic skin flaps. METHODS:Peli1fl/fl and Peli1-/- mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Tissues from the left ventricular risk area were collected at different time points post-MI. In addition, Peli1fl/fl and Peli1-/- mice were also subjected to permanent ligation of the right femoral artery followed by motor function scores, Doppler analysis for blood perfusion and immunohistochemical analysis. RESULTS:Global Peli1 knockout exacerbated myocardial dysfunction, 30 and 60 days after MI compared to wild type (WT) mice as measured by echocardiogram. In addition, Peli1-/- mice also showed decreased motor function scores and perfusion ratios compared with Peli1fl/fl mice 28 days after the induction of HLI. The use of Peli1 in adenoviral gene therapy following HLI in CD1 mice improved the perfusion ratio at 28 days compared to Ad.LacZ-injected mice. CONCLUSION:These results suggest new insights into the protective role of Peli1 on ischemic tissues and its influence on survival signaling.

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简介:在本研究中,我们旨在探讨Pellino-1(Peli1)在使用Peli1整体敲除小鼠(Peli1-/-)诱导心肌梗死(MI)和后肢缺血(HLI)后新生血管形成中的功能。最近,我们发现Peli1,一种E3泛素连接酶,可诱导血管生成并提高生存能力,并减少缺血性皮瓣的坏死。
方法:对Peli1fl / fl和Peli1-/-小鼠进行永久性结扎左冠状动脉前降支(LAD)或假手术(S)。在MI后的不同时间点收集来自左心室风险区的组织。此外,还对Peli1fl / fl和Peli1-/-小鼠进行永久性右股动脉结扎,然后进行运动功能评分,多普勒血流灌注分析和免疫组化分析。
结果:通过超声心动图测量,与野生型(WT)小鼠相比,MI后30天和60天,整体Peli1基因敲除加重了心肌功能障碍。此外,诱导HLI后28天,与Peli1fl / fl小鼠相比,Peli1-/-小鼠还显示出降低的运动功能评分和灌注比。与注射Ad.LacZ的小鼠相比,在CD1小鼠中进行HLI后在腺病毒基因治疗中使用Peli1可以改善28天的灌注率。
结论:这些结果提示了Peli1对缺血组织的保护作用及其对生存信号的影响的新见解。

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