The influence of redox modulation on hypoxic endothelial cell metabolic and proteomic profiles through a small thiol ‐based compound tuning glutathione and thioredoxin systems

The intracellular redox state of endothelial cells facing low oxygen and oxidative stress was regulated via the pro-glutathione molecule I-152, a co-drug of N-acetylcysteine and cysteamine. The principal redox couples, GSH/GSSG, and NAD(P)+/NAD(P)H were affected by hypoxia and in turn, modulated with I-152. Glutathione and thioredoxin-related pathways were enhanced after treatment and ROS production was alleviated. Strategies to fine-tune the redox balance could ameliorate the cell response to hypoxic environments. AbstractReduction in oxygen levels is a key feature in the physiology of the bone marrow (BM) niche where hematopoiesis occurs. The BM niche is a highly vascularized tissue and endothelial cells (ECs) support and regulate blood cell formation from hematopoietic stem cells (HSCs). While in vivo studies are limited, ECs when cultured in vitro at low O2 (<5%), fail to support functional HSC maintenance due to oxidative environment. Therefore, changes in EC redox status induced by antioxidant molecules may lead to alterations in the cellular response to hypoxia likely favoring HSC self-renewal. To evaluate the impact of redox regulation, HUVEC, exposed for 1, 6, and 24  h to 3% O2 were treated with N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine (I-152). Metabolomic analyses revealed that I-152 increased glutathione levels and influenced the metabolic profiles interconnected with the glutathione system and the redox couples NAD(P)+/NAD(P)H. mRNA analysis showed a lowe...
Source: BioFactors - Category: Biochemistry Authors: Tags: RESEARCH ARTICLE Source Type: research