Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba 5000, Argentina.
Cells. 2023 Feb 2;12(3):494. doi: 10.3390/cells12030494.
Inflammation and oxidative and nitrosative stress are involved in the pathogenesis of proliferative retinopathies (PR). In PR, a loss of balance between pro-angiogenic and anti-angiogenic factors favors the secretion of vascular endothelial growth factor (VEGF). This vascular change results in alterations in the blood-retinal barrier, with extravasation of plasma proteins such as α-macroglobulin (αM) and gliosis in Müller glial cells (MGCs, such as MIO-M1). It is well known that MGCs play important roles in healthy and sick retinas, including in PR. Nitro-fatty acids are electrophilic lipid mediators with anti-inflammatory and cytoprotective properties. Our aim was to investigate whether nitro-oleic acid (NO-OA) is beneficial against oxidative stress, gliosis, and the pro-angiogenic response in MGCs. Pure synthetic NO-OA increased HO-1 expression in a time- and concentration-dependent manner, which was abrogated by the Nrf2 inhibitor trigonelline. In response to phorbol 12-myristate 13-acetate (PMA) and lipopolysaccharide (LPS), NO-OA prevented the ROS increase and reduced the gliosis induced by αM. Finally, when hypoxic MGCs were incubated with NO-OA, the increase in VEGF mRNA expression was not affected, but under hypoxia and inflammation (IL-1β), NO-OA significantly reduced VEGF mRNA levels. Furthermore, NO-OA inhibited endothelial cell (BAEC) tubulogenesis. Our results highlight NO-OA's protective effect on oxidative damage, gliosis; and the exacerbated pro-angiogenic response in MGCs.
炎症、氧化应激和硝化应激都参与了增生性视网膜病变（PR）的发病机制。在 PR 中，促血管生成和抗血管生成因子之间的平衡失调会促进血管内皮生长因子（VEGF）的分泌。这种血管变化导致血视网膜屏障发生改变，血浆蛋白如α巨球蛋白（αM）外渗和 Müller 胶质细胞（MGCs，如 MIO-M1）发生神经胶质增生。众所周知，MGCs 在健康和患病的视网膜中发挥着重要作用，包括在 PR 中。硝酰基脂肪酸是具有抗炎和细胞保护特性的亲电脂质介质。我们的目的是研究硝酰基油酸（NO-OA）是否有益于对抗 MGCs 中的氧化应激、神经胶质增生和促血管生成反应。纯合成的 NO-OA 以时间和浓度依赖的方式增加 HO-1 的表达，而 Nrf2 抑制剂三叶草素则消除了这种作用。在佛波醇 12-肉豆蔻酸 13-醋酸盐（PMA）和脂多糖（LPS）的刺激下，NO-OA 可防止 ROS 增加，并减少由αM 引起的神经胶质增生。最后，当缺氧的 MGCs 用 NO-OA 孵育时，VEGF mRNA 表达的增加不受影响，但在缺氧和炎症（IL-1β）下，NO-OA 显著降低了 VEGF mRNA 水平。此外，NO-OA 抑制了内皮细胞（BAEC）的小管形成。我们的研究结果强调了 NO-OA 对氧化损伤、神经胶质增生和 MGCs 中促血管生成反应的加剧的保护作用。
