Modulatory Effect of Rosmarinic Acid on H2O2-Induced Adaptive Glycolytic Response in Dermal Fibroblasts

Abstract

Oxidative stress induces the adaptive response and alteration of energy metabolism across human cell types. Dermal fibroblasts shift their energy system to overload anaerobic glycolysis when exposed to sub-lethal hydrogen peroxide (H2O2). However, oxidative stress levels in the cells can be depleted by antioxidants, and such cellular changes can therefore be modulated. The present study aimed to investigate the modulatory effect of rosmarinic acid (a polyphenol antioxidant) against H2O2-induced reactive oxygen species (ROS) and the glycolytic adaptive response in fibroblasts. The results showed that H2O2 caused a significant ROS increase in the cells, and pre-treatment with rosmarinic acid (5–50 µM) decreased ROS significantly in the presence of glutathione. Rosmarinic acid modulated the adaptive response in H2O2-treated cells by decreasing glucose consumption and lactate production. The rosmarinic acid also recovered intracellular ATP and decreased NADPH production via the pentose phosphate pathway. Several glycolytic enzymes, including hexokinase-2 (HK-2), phosphofructokinase-2 (PFK-2), and lactate dehydrogenase A (LDHA), were downregulated in cells treated with rosmarinic acid. Furthermore, the key antioxidant enzymes: glutathione-disulfide reductase (GSR), glutathione peroxidase-1 (GPx-1), and peroxiredoxin-1 (Prx-1) and redox protein thioredoxin-1 (Trx-1) were upregulated in treated cells compared to control cells. To sum up, the rosmarinic acid could be used as an antioxidant against H2O2-induced adaptive responses in fibroblasts by modulating glucose metabolism, glycolytic genes, and GSH production. The present work indicates that rosmarinic acid holds promise in cell-based research applications for combating ROS and enhancing dermal fibroblast health.