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

2016 ◽  
Vol 130 (23) ◽  
pp. 2181-2198 ◽  
Author(s):  
Yujia Yuan ◽  
Meimei Shi ◽  
Lan Li ◽  
Jingping Liu ◽  
Bo Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Mesenchymal Stem Cell ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Mitochondrial Bioenergetics ◽  
Sirt1 Expression

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.

scholarly journals How AMPK and PKA Interplay to Regulate Mitochondrial Function and Survival in Models of Ischemia and Diabetes

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jingdian Zhang ◽  
Yumeng Wang ◽  
Xiaofeng Liu ◽  
Ruben K. Dagda ◽  
Ying Zhang
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Cardiovascular Diseases ◽  
Protein Kinase ◽  
Cell Survival ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Temporal Dynamics ◽  
Protein Translation ◽  
Conservation Of Energy

Adenosine monophosphate-activated protein kinase (AMPK) is a conserved, redox-activated master regulator of cell metabolism. In the presence of oxidative stress, AMPK promotes cytoprotection by enhancing the conservation of energy by suppressing protein translation and by stimulating autophagy. AMPK interplays with protein kinase A (PKA) to regulate oxidative stress, mitochondrial function, and cell survival. AMPK and dual-specificity A-kinase anchoring protein 1 (D-AKAP1), a mitochondrial-directed scaffold of PKA, interact to regulate mitochondrial function and oxidative stress in cardiac and endothelial cells. Ischemia and diabetes, a chronic disease that increases the onset of cardiovascular diseases, suppress the cardioprotective effects of AMPK and PKA. Here, we review the molecular mechanisms by which AMPK and D-AKAP1/PKA interplay to regulate mitochondrial function, oxidative stress, and signaling pathways that prime endothelial cells, cardiac cells, and neurons for cytoprotection against oxidative stress. We discuss recent literature showing how temporal dynamics and localization of activated AMPK and PKA holoenzymes play a crucial role in governing cellular bioenergetics and cell survival in models of ischemia, cardiovascular diseases, and diabetes. Finally, we propose therapeutic strategies that tout localized PKA and AMPK signaling to reverse mitochondrial dysfunction, oxidative stress, and death of neurons and cardiac and endothelial cells during ischemia and diabetes.

Mesenchymal Stem Cell and Oxygen Modulate the Cocultured Endothelial Cells in the Presence of Magnesium Degradation Products

2021 ◽  
Vol 4 (3) ◽  
pp. 2398-2407
Author(s):  
Lei Xu ◽  
Regine Willumeit-Römer ◽  
Bérengère J. C. Luthringer-Feyerabend
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Degradation Products

scholarly journals Synergy of molecularly mobile polyrotaxane surfaces with endothelial cell co-culture for mesenchymal stem cell mineralization

RSC Advances ◽  
2021 ◽  
Vol 11 (30) ◽  
pp. 18685-18692
Author(s):  
Hiroki Masuda ◽  
Yoshinori Arisaka ◽  
Masahiro Hakariya ◽  
Takanori Iwata ◽  
Tetsuya Yoda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Endothelial Cell ◽  
Mesenchymal Stem Cell ◽  
Molecular Mobility ◽  
Culture System

Molecular mobility of polyrotaxane surfaces promoted mineralization in a co-culture system of mesenchymal stem cells and endothelial cells.

scholarly journals High stretch induces endothelial dysfunction accompanied by oxidative stress and actin remodeling in human saphenous vein endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
T. Girão-Silva ◽  
M. H. Fonseca-Alaniz ◽  
J. C. Ribeiro-Silva ◽  
J. Lee ◽  
N. P. Patil ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Saphenous Vein ◽  
Saphenous Vein Graft ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Human Saphenous Vein ◽  
Actin Remodeling

AbstractThe rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin’s nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.

Oxidative stress in diabetes-induced endothelial dysfunction involvement of nitric oxide and protein kinase C

2003 ◽  
Vol 35 (6) ◽  
pp. 683-694 ◽  
Author(s):  
Flavia Pricci ◽  
Gaetano Leto ◽  
Lorena Amadio ◽  
Carla Iacobini ◽  
Samantha Cordone ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Kinase C

Abstract MP30: Circulating Sars-cov-2 Spike Protein 1 Causes Microarteriolar Oxidative Stress, Endothelial Dysfunction And Enhanced Thromboxane And Endothelin Contractility That Are Prevented By Spironolactone.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Dan Wang ◽  
Christopher S Wilcox
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Fluorescence Microscopy ◽  
Vascular Dysfunction ◽  
Microvascular Complications ◽  
Spike Protein ◽  
Ros Generation ◽  
Intravenous Injections ◽  
Novel Model

Introduction and hypothesis: Following bodily entry, the SARS-CoV-2 virus undergoes pulmonary replication with release of circulating viral spike protein 1 (SP1) into the bloodstream. Uptake of SP1 by endothelial cells might provoke vascular dysfunction and thrombosis. We hypothesized that spironolactone could prevent microvascular complications from circulating SP1 in COVID-19. Methods: male C57Bl/6 mice received spironolactone (100 mg · kg -1 · d -1 PO x 3d) or vehicle and intravenous injections of recombinant full-length human SP1 (10 μg per mouse) or vehicle. They were euthanized after 3 days. Mesenteric resistant arterioles (n=4 per group) were dissected and mounted on isometric myographs. Acetylcholine-induced EDRF responses and L-NAME-inhibitable NO generation (DAF-FM fluorescence) were studied in pre-constricted vessels and contraction to endothelin 1 (ET1) or thromboxane (U-46, 619) and ET1-induced ROS (PEG-SOD inhibitable ethidium: dihydroethidium fluorescence) were studied by fluorescence microscopy in other vessels. Results: SP1 reduced acetylcholine-induced EDRF (17 ± 3 vs 27 ± 5 % mean ± sem; P < 0.05) and NO generation (0.21 ± 0.03 vs 0.36 ± 0.04, F 1 /F 0 ; P < 0.05) while increasing contraction to ET1 (10 -7 mol·l -1 : 124 ± 13 vs 89 ± 4 %; P < 0.05) and U-46, 619 (10 -6 mol·l -1 :114± 5 vs 87± 6 %; P < 0.05) and ET1-induced ROS generation(0.30± 0.08 vs 0.09± 0.03; P < 0.05). Spironolactone did not modify any of these responses in vessels from normal mice but prevented all the effects of SP1. Conclusion: these preliminary studies provide a novel model to study COVID-19 vasculopathy. They indicate that spironolactone can provide protection from microvascular oxidative stress, endothelial dysfunction and enhanced contractility and might thereby moderate COVID-19 complications.

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