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  • Title: Phosphocreatine protects endothelial cells from Methylglyoxal induced oxidative stress and apoptosis via the regulation of PI3K/Akt/eNOS and NF-κB pathway.
    Author: Chu P, Han G, Ahsan A, Sun Z, Liu S, Zhang Z, Sun B, Song Y, Lin Y, Peng J, Tang Z.
    Journal: Vascul Pharmacol; 2017 Apr; 91():26-35. PubMed ID: 27590258.
    Abstract:
    Methylglyoxal (MGO), an active metabolite of glucose, can cause cellular injury which has an affinity for the progression of diabetes-associated atherosclerosis. Phosphocreatine (PCr) is a well-known high-energy phosphate compound. However, its protective effects and mechanism in the formation of a diabetes-associated atherosclerosis have not been clarified. In the present study, we investigated whether PCr could prevent MGO-induced apoptosis in human umbilical vascular endothelial cells (HUVECs) and explored the possible mechanisms. Cells were pre-treated with PCr and then stimulated with MGO. Cell morphology, cytotoxicity and apoptosis were assessed by light microscopy, MTT assay, and Annexin V-FITC respectively. Apoptotic-related proteins were evaluated by Western blotting. Reactive oxygen species (ROS) generation, intracellular calcium and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results showed that PCr dose-dependently prevented MGO associated HUVEC cytotoxicity and suppressed MGO activated ROS generation as well as apoptotic biochemical changes such as lactate dehydrogenase, malondialdehyde leakage, loss of MMP, decreased Bcl-2/Bax protein ratio, levels of caspase-3 and 9. In addition, the antiapoptotic effect of PCr enhanced p-Akt/Akt protein ratio, NO synthase (eNOS) activation, NO production and cGMP levels and also was partially suppressed by a PI3K inhibitor (LY294002). Furthermore, PCr also inhibited MGO-induced transcriptional activity of Nuclear factor kappa B (NFκB). In conclusion, our data described that PCr exerts an antiapoptotic effect in HUVECs exposed to oxidative stress by MGO through the mitochondrial pathway and the modulation of PI3K/Akt/eNOS and NF-κB signaling pathway. Thus, it might be a candidate therapeutic agent for diabetic-associated cardiovascular diseases.
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