Lactucaxanthin protects retinal pigment epithelium from hyperglycemia-regulated hypoxia/ER stress/VEGF pathway mediated angiogenesis in ARPE-19 cell and rat model.

Hyperglycemia mediated perturbations in biochemical pathways induce angiogenesis in diabetic retinopathy
(DR) pathogenesis. The present study aimed to investigate the protective effects of lactucaxanthin, a predominant
lettuce carotenoid, on hyperglycemia-mediated activation of angiogenesis in vitro and in vivo diabetic
model. ARPE-19 cells cultured in 30 mM glucose concentration were treated with lactucaxanthin (5 μM and 10
μM) for 48 h. They were assessed for antioxidant enzyme activity, mitochondrial membrane potential, reactive
oxygen species, and cell migration. In the animal experiment, streptozotocin-induced diabetic male Wistar rats
were gavaged with lactucaxanthin (200 μM) for 8 weeks. Parameters like animal weight gain, feed intake, water
intake, urine output, and fasting blood glucose level were monitored. In both models, lutein-treated groups were
considered as a positive control. Hyperglycemia-mediated angiogenic marker expressions in ARPE-19 and retina
of diabetic rats were quantified through the western blot technique. Expression of hypoxia, endoplasmic reticulum
stress markers, and vascular endothelial growth factor were found to be augmented in the hyperglycemia
group compared to control (P < 0.05). Hyperglycemia plays a crucial role in increasing cellular migration and
reactive oxygen species besides disrupting tight junction protein. Compared to lutein, lactucaxanthin aids retinal
pigment epithelium (RPE) function from hyperglycemia-induced stress conditions via downregulating angiogenesis
markers expression. Lactucaxanthin potentiality observed in protecting tight junction protein expression
via modulating reactive oxygen species found to conserve RPE integrity. Results demonstrate that lactucaxanthin
exhibits robust anti-angiogenic activity for the first time and, therefore, would be useful as an alternative therapy
to prevent or delay DR progression.