Laboratorio de Citoarquitectura y Plasticidad Neuronal, Instituto de Investigaciones Cardiológicas "Prof. Dr. Alberto C. Taquini" (ININCA), Facultad de Medicina (UBA-CONICET), Buenos Aires, Argentina; Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Argentina.
Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Argentina.
Neuroscience. 2020 Jan 15;425:235-250. doi: 10.1016/j.neuroscience.2019.11.011. Epub 2019 Nov 27.
Thioredoxin family proteins are key modulators of cellular redox regulation and have been linked to several physiological functions, including the cellular response to hypoxia-ischemia. During perinatal hypoxia-ischemia (PHI), the central nervous system is subjected to a fast decrease in O and nutrients with a subsequent reoxygenation that ultimately leads to the production of reactive species impairing physiological redox signaling. Particularly, the retina is one of the most affected tissues, due to its high oxygen consumption and exposure to light. One of the main consequences of PHI is retinopathy of prematurity, comprising changes in retinal neural and vascular development, with further compensatory mechanisms that can ultimately lead to retinal detachment and blindness. In this study, we have analyzed long-term changes that occur in the retina using two well established in vivo rat PHI models (perinatal asphyxia and carotid ligation model), as well as the ARPE-19 cell line that was exposed to hypoxia and reoxygenation. We observed significant changes in the protein levels of the cytosolic oxidoreductase thioredoxin 1 (Trx1) in both animal models and a cell model. Knock-down of Trx1 in ARPE-19 cells affected cell morphology, proliferation and the levels of specific differentiation markers. Administration of recombinant Trx1 decreased astrogliosis and improved delayed neurodevelopment in animals exposed to PHI. Taken together, our results suggest therapeutical implications for Trx1 in retinal damage induced by hypoxia-ischemia during birth.
硫氧还蛋白家族蛋白是细胞氧化还原调节的关键调节剂，与许多生理功能有关，包括细胞对缺氧-缺血的反应。在围产期缺氧-缺血（PHI）期间，中枢神经系统会迅速减少氧气和营养物质，随后再氧化，最终导致活性物质的产生，损害生理氧化还原信号。特别是，由于其高耗氧量和暴露在光线下，视网膜是受影响最严重的组织之一。PHI 的主要后果之一是早产儿视网膜病变，包括视网膜神经和血管发育的变化，以及进一步的代偿机制，最终可导致视网膜脱离和失明。在这项研究中，我们使用两种成熟的体内大鼠 PHI 模型（围产期窒息和颈动脉结扎模型）以及暴露于缺氧和再氧化的 ARPE-19 细胞系分析了视网膜中发生的长期变化。我们观察到两种动物模型和细胞模型中细胞溶质氧化还原酶硫氧还蛋白 1（Trx1）的蛋白水平发生了显著变化。ARPE-19 细胞中 Trx1 的敲低会影响细胞形态、增殖和特定分化标志物的水平。在暴露于 PHI 的动物中，给予重组 Trx1 可减少星形胶质细胞增生并改善延迟性神经发育。总之，我们的结果表明，Trx1 在出生时缺氧-缺血引起的视网膜损伤中具有治疗意义。
