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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 α₂-macroglobulin (α₂M) 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 (NO₂-OA) is beneficial against oxidative stress, gliosis, and the pro-angiogenic response in MGCs. Pure synthetic NO₂-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), NO₂-OA prevented the ROS increase and reduced the gliosis induced by α₂M. Finally, when hypoxic MGCs were incubated with NO₂-OA, the increase in VEGF mRNA expression was not affected, but under hypoxia and inflammation (IL-1β), NO₂-OA significantly reduced VEGF mRNA levels. Furthermore, NO₂-OA inhibited endothelial cell (BAEC) tubulogenesis. Our results highlight NO₂-OA’s protective effect on oxidative damage, gliosis; and the exacerbated pro-angiogenic response in MGCs.