Protein Phosphatase Magnesium Dependent 1A Governs the Wound Healing-Inflammation-Angiogenesis Cross Talk on Injury
Protein Phosphatase Magnesium Dependent 1A Governs the Wound Healing-Inflammation-Angiogenesis Cross Talk on Injury
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DOI：
10.1016/j.ajpath.2014.07.022
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发表时间：
2014-11-01
影响因子：
6
通讯作者：
Lavi, Sara
中科院分区：
文献类型：
--
作者：
Dvashi, Zeev;Shalom, Hadas Sar;Lavi, Sara
蛋白磷酸酶镁依赖蛋白1A(PPM1A)与纤维化和皮肤损伤有关。我们建立了PPM1A基因敲除小鼠，以研究PPM1A在伤口愈合-炎症-血管生成串连中的作用。利用眼部碱烧伤模型系统研究了PPM1a在这些过程中的作用。在损伤的角膜中，PPM1A的缺失导致炎症反应增强，基质细胞反式激活，纤维化，p38丝裂原活化蛋白激酶磷酸化增加，转化生长因子-β相关基因(包括Acta2，TGF-β，col1，MMP9和VEGF)的表达增加，继而导致新生血管形成。在缺乏PPM1A的情况下，增强血管生成是PPM1A基因敲除小鼠在皮下注射Matrigel时体内发生的一般过程，以及在体外主动脉环Matrigel培养中发生的。利用原代培养的角质形成细胞和各种实验方法，我们发现p38是一种很受欢迎的PPM1A底物，PPM1A通过其去磷酸化参与了转化生长因子-β信号级联反应的调节，这是炎症和血管生成过程的标志。总体而言，本文介绍的研究将PPM1A定位为小鼠伤口愈合-炎症-血管生成轴的新参与者，揭示了其在损伤的动态平衡中的关键作用，并强调了其作为病理条件下的治疗介质的潜力，如炎症和血管生成障碍，包括癌症。
Protein phosphatase magnesium dependent 1A (PPM1A) has been implicated in fibrosis and skin wounding. We generated PPM1A knockout mice to study the role of PPM1A in the wound healing-inflammation-angiogenesis cross talk. The role of PPM1A in these processes was studied using the ocular alkali burn model system. In the injured cornea the absence of PPM1A led to enhanced inflammatory response, stromal keratocyte transactivation, fibrosis, increased p38 mitogen-activated protein kinase phosphorylation, elevated expression of transforming growth factor-beta-related genes (including Acta2, TGF-beta, Col1, MMP9, and VEGF) and subsequently to neovascularization. Augmented angiogenesis in the absence of PPM1A is a general process occurring in vivo in PPM1A knockout mice upon subcutaneous Matrigel injection and ex vivo in aortic ring Matrigel cultures. Using primary keratocyte cultures and various experimental approaches, we found that phospho-p38 is a favored PPM1A substrate and that by its dephosphorylation PPM1A participates in the regulation of the transforming growth factor-beta signaling cascade, the hallmark of inflammation and the angiogenic process. On the whole, the studies presented here position PPM1A as a new player in the wound healing-inflammation-angiogenesis axis in mouse, reveal its crucial rote in homeostasis on injury, and highlight its potential as a therapeutic mediator in pathologic conditions, such as inflammation and angiogenesis disorders, including cancer.