Vasculopathy is a major complication of diabetes. Impaired mitochondrial bioenergetics and biogenesis due to oxidative stress are a critical causal factor for diabetic endothelial dysfunction. Sirt1, an NAD+-dependent enzyme, is known to play an important protective role through deacetylation of many substrates involved in oxidative phosphorylation and reactive oxygen species generation. Mesenchymal stem cell-conditioned medium (MSC-CM) has emerged as a promising cell-free therapy due to the trophic actions of mesenchymal stem cell (MSC)-secreted molecules. In the present study, we investigated the therapeutic potential of MSC-CMs in diabetic endothelial dysfunction, focusing on the Sirt1 signalling pathway and the relevance to mitochondrial function. We found that high glucose-stimulated MSC-CM attenuated several glucotoxicity-induced processes, oxidative stress and apoptosis of endothelial cells of the human umbilical vein. MSC-CM perfusion in diabetic rats ameliorated compromised aortic vasodilatation and alleviated oxidative stress in aortas. We further demonstrated that these effects were dependent on improved mitochondrial function and up-regulation of Sirt1 expression. MSC-CMs activated the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), leading to direct interaction between Akt and Sirt1, and subsequently enhanced Sirt1 expression. In addition, both MSC-CM and Sirt1 activation could increase the expression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), as well as increase the mRNA expression of its downstream, mitochondrial, biogenesis-related genes. This indirect regulation was mediated by activation of AMP-activated protein kinase (AMPK). Overall our findings indicated that MSC-CM had protective effects on endothelial cells, with respect to glucotoxicity, by ameliorating mitochondrial dysfunction via the PI3K/Akt/Sirt1 pathway, and Sirt1 potentiated mitochondrial biogenesis, through the Sirt1/AMPK/PGC-1α pathway.
Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway
- Views Icon Views
- Share Icon Share
Yujia Yuan, Meimei Shi, Lan Li, Jingping Liu, Bo Chen, Younan Chen, Xingxing An, Shuyun Liu, Ruixi Luo, Dan Long, Wengeng Zhang, Philip Newsholme, Jingqiu Cheng, Yanrong Lu; Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway. Clin Sci (Lond) 1 December 2016; 130 (23): 2181–2198. doi: https://doi.org/10.1042/CS20160235
Download citation file: