Potential compensation among group I PAK members in hindlimb ischemia and wound healing.
Potential compensation among group I PAK members in hindlimb ischemia and wound healing.
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DOI：
10.1371/journal.pone.0112239
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Parise LV
中科院分区：
文献类型：
--
作者：
Elsherif L;Ozler M;Zayed MA;Shen JH;Chernoff J;Faber JE;Parise LV
PAK是调节细胞骨架动力学和细胞迁移的丝氨酸/苏氨酸激酶。PAK 1通过与小EF手蛋白CIB 1或Rho GTP酶Rac 1或Cdc 42结合而被激活。PAK 1在血管生成中的作用仅基于体外研究确定，其在体内血管生成中的作用从未被研究过。在这里，我们测试的假设，PAK 1是缺血性新血管形成（动脉生成和血管生成）和伤口愈合的一个重要的调节器使用一个全球PAK 1基因敲除小鼠。采用单侧后肢缺血评估新生血管形成。我们发现，在后肢缺血后的整个21天期间，6-8周龄PAK 1 −/−和PAK 1 +/+小鼠之间的足底灌注、肢体使用和外观没有显著差异;然而，在16周龄PAK 1 −/−小鼠中观察到轻微延迟愈合。此外，PAK 1 −/−小鼠的伤口愈合率（通过耳穿孔试验评估）未发生变化。然而，令人惊讶的是，我们观察到PAK 1-/-而不是PAK 1 +/+小鼠缺血腓肠肌组织中PAK 2表达和磷酸化显著增加。此外，我们在PAK 1 −/−小鼠后肢缺血性损伤后的缺血性和非缺血性肌肉中观察到更高水平的活化ERK 2，而不是AKT。第一组PAK抑制剂，IPA 3，显着抑制内皮细胞发芽从主动脉环在PAK 1-/-和PAK 1 +/+小鼠，这意味着PAK 2是一个潜在的贡献者这一过程。总之，我们的数据表明，虽然PAK 1有可能有助于新血管形成和伤口愈合，但PAK 2可能在PAK 1缺乏时进行功能补偿。
PAKs are serine/threonine kinases that regulate cytoskeletal dynamics and cell migration. PAK1 is activated by binding to the small EF hand protein, CIB1, or to the Rho GTPases Rac1 or Cdc42. The role of PAK1 in angiogenesis was established based only on in vitro studies and its role in angiogenesis in vivo has never been examined. Here we tested the hypothesis that PAK1 is an essential regulator of ischemic neovascularization (arteriogenesis and angiogenesis) and wound healing using a global PAK1 knockout mouse. Neovascularization was assessed using unilateral hindlimb ischemia. We found that plantar perfusion, limb use and appearance were not significantly different between 6–8 week old PAK1−/− and PAK1+/+ mice throughout the 21-day period following hindlimb ischemia; however a slightly delayed healing was observed in 16 week old PAK1−/− mice. In addition, the wound healing rate, as assessed with an ear punch assay, was unchanged in PAK1−/− mice. Surprisingly, however, we observed a notable increase in PAK2 expression and phosphorylation in ischemic gastrocnemius tissue from PAK1−/− but not PAK1+/+ mice. Furthermore, we observed higher levels of activated ERK2, but not AKT, in ischemic and non-ischemic muscle of PAK1−/− mice upon hindlimb ischemic injury. A group I PAK inhibitor, IPA3, significantly inhibited endothelial cell sprouting from aortic rings in both PAK1−/− and PAK1+/+ mice, implying that PAK2 is a potential contributor to this process. Taken together, our data indicate that while PAK1 has the potential to contribute to neovascularization and wound healing, PAK2 may functionally compensate when PAK1 is deficient.
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影响因子：
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