Mesenchymal Stem Cells-Conditioned Media Ameliorates Diabetic Endothelial dysfunction by Improving Mitochondrial Bioenergetics via the Sirt1/AMPK/PGC-1{alpha} Pathway

Vasculopathy is a major complication of diabetes. Impaired mitochondrial bioenergetics and biogenesis due to oxidative stress is a critical causal factor for diabetic endothelial dysfunction. Sirt1, a NAD+-dependent enzyme, is known to play an important protective role through deacetylation of many substrates involved in oxidative phosphorylation and reactive oxygen species (ROS) generation. Conditioned medium from mesenchymal stem cells (MSCs-CM) has emerged as a promising cell-free therapy due to the trophic actions of MSCs secreted molecules. Here, we investigated the therapeutic potential of MSCs-CM on diabetic endothelial dysfunction, focusing on Sirt1 signaling pathway and the relevance to mitochondrial function. We found that high glucose stimulated-MSCs-CM attenuated several glucotoxicity induced processes, oxidative stress and apoptosis of human umbilical vein endothelial cells. MSCs-CM perfusion in diabetic rats ameliorated compromised aortic vasodilatation and alleviated oxidative stress in aorta. We further demonstrated that these effects were dependent on improved mitochondrial function, and up-regulation of Sirt1 expression. MSCs-CM activated the phosphorylation of PI3K and AKT, leading to direct interaction between AKT and Sirt1, and subsequently enhanced Sirt1 expression. Additionally, both MSCs-CM and Sirt1 activation were able to increase the expression of peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), as well as incre...

Source: Clinical Science - September 8, 2016 Category: Biomedical Science Authors: Yuan, Y., Shi, M., Li, L., Liu, J., Chen, B., Chen, Y., An, X., Liu, S., Luo, R., Long, D., Zhang, W., Newsholme, P., Cheng, J., Lu, Y. Tags: PublishAheadOfPrint Source Type: research