Endothelial dysfunction

Clin Sci (Lond). 2016 Sep 9. pii: CS20160235. [Epub ahead of print]

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

Yuan Y¹, Shi M¹, Li L¹, Liu J¹, Chen B¹, Chen Y¹, An X¹, Liu S¹, Luo R¹, Long D¹, Zhang W¹, Newsholme P², Cheng J¹, Lu Y³.

Author information

¹Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Center, West China Hospital, Sichuan University., Chengdu, China.

²Curtin University, Building 308 Room 122, GPO Box U1987, Perth, Perth, 6845, United States.

³Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Center, West China Hospital, Sichuan University., Chengdu, China

Abstract

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 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 MSCs-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 Sirt1/AMPK/PGC-1α pathway.

KEYWORDS:

Mesenchymal stem cells-conditioned media; endothelial dysfunction; mitochondrial biogenesis; sirtuins