Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway.

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.

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 ... -  《-》

The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocyte via the AMPK-Sirt1-Pgc-1α signalling pathway.

Yang X ，Liu Q ，Li Y ，Tang Q ，Wu T ，Chen L ，Pu S ，Zhao Y ，Zhang G ，Huang C ，Zhang J ，Zhang Z ，Huang Y ，Zou M ，Shi X ，Jiang W ，Wang R ，He J ... -  《-》

Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1α deacetylation.

Fang WJ ，Wang CJ ，He Y ，Zhou YL ，Peng XD ，Liu SK ... -  《-》

Grape seed proanthocyanidin extracts ameliorate podocyte injury by activating peroxisome proliferator-activated receptor-γ coactivator 1α in low-dose streptozotocin-and high-carbohydrate/high-fat diet-induced diabetic rats.

Bao L ，Cai X ，Dai X ，Ding Y ，Jiang Y ，Li Y ，Zhang Z ，Li Y ... -  《-》

Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1α axis in vitro.

Cai X ，Bao L ，Ren J ，Li Y ，Zhang Z ... -  《-》