PMID- 27613156
OWN - NLM
STAT- MEDLINE
DCOM- 20170824
LR  - 20181203
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 130
IP  - 23
DP  - 2016 Dec 1
TI  - Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial 
      dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1alpha 
      pathway.
PG  - 2181-2198
AB  - 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 gamma co-activator-1alpha (PGC-1alpha), 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-1alpha pathway.
CI  - (c) 2016 The Author(s). published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Yuan, Yujia
AU  - Yuan Y
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Shi, Meimei
AU  - Shi M
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Li, Lan
AU  - Li L
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Liu, Jingping
AU  - Liu J
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Chen, Bo
AU  - Chen B
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Chen, Younan
AU  - Chen Y
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
AD  - School of Biomedical Sciences, CHIRI Biosciences, Curtin University, GPO Box 
      U1987, Perth, Western Australia, Australia.
FAU - An, Xingxing
AU  - An X
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Liu, Shuyun
AU  - Liu S
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Luo, Ruixi
AU  - Luo R
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Long, Dan
AU  - Long D
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Zhang, Wengeng
AU  - Zhang W
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Newsholme, Philip
AU  - Newsholme P
AD  - School of Biomedical Sciences, CHIRI Biosciences, Curtin University, GPO Box 
      U1987, Perth, Western Australia, Australia.
FAU - Cheng, Jingqiu
AU  - Cheng J
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China.
FAU - Lu, Yanrong
AU  - Lu Y
AD  - Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative 
      Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, 
      People's Republic of China luyanrong@scu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20160909
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - AMP-Activated Protein Kinases/genetics/*metabolism
MH  - Animals
MH  - Apoptosis
MH  - Culture Media, Conditioned/metabolism/*pharmacology
MH  - Diabetes Mellitus, Experimental/genetics/metabolism/physiopathology/*therapy
MH  - Glucose/metabolism
MH  - Human Umbilical Vein Endothelial Cells/cytology/metabolism
MH  - Humans
MH  - Male
MH  - Mesenchymal Stem Cells/cytology/*metabolism
MH  - Mitochondria/genetics/*metabolism
MH  - Oxidative Stress
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Sirtuin 1/genetics/*metabolism
OTO - NOTNLM
OT  - endothelial dysfunction
OT  - mesenchymal stem cell-conditioned media
OT  - mitochondrial biogenesis
OT  - sirtuins
EDAT- 2016/11/01 06:00
MHDA- 2017/08/25 06:00
CRDT- 2016/09/11 06:00
PHST- 2016/03/29 00:00 [received]
PHST- 2016/09/05 00:00 [accepted]
PHST- 2016/11/01 06:00 [pubmed]
PHST- 2017/08/25 06:00 [medline]
PHST- 2016/09/11 06:00 [entrez]
AID - CS20160235 [pii]
AID - 10.1042/CS20160235 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2016 Dec 1;130(23):2181-2198. doi: 10.1042/CS20160235. Epub 2016 
      Sep 9.