Phosphocreatine protects endothelial cells from Methylglyoxal induced oxidative stress and apoptosis via the regulation of PI3K/Akt/eNOS and NF-κB pathway

甲基乙二醛 氧化应激 蛋白激酶B 细胞凋亡 PI3K/AKT/mTOR通路 伊诺斯 化学 磷酸肌酸 活性氧 膜联蛋白 细胞生物学 生物化学 分子生物学 生物 一氧化氮合酶 内分泌学 能量代谢
作者
Peng Chu,Guozhu Han,Anil Ahsan,Zhengwu Sun,Shumin Liu,Zong‐Hui Zhang,Bin Sun,Yanlin Song,Yuan Lin,Jinyong Peng,Zeyao Tang
出处
期刊:Vascular Pharmacology [Elsevier]
卷期号:91: 26-35 被引量:48
标识
DOI:10.1016/j.vph.2016.08.012
摘要

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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