Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression

• Published in: Cell death & disease 2015-07, Vol.6 (7), p.e1827-e1827
• Main Authors: Liu, J, Bi, X, Chen, T, Zhang, Q, Wang, S-X, Chiu, J-J, Liu, G-S, Zhang, Y, Bu, P, Jiang, F
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 38/35; 38/89; 42/109; 42/44; 631/443/592; 631/80/82/39; 631/80/86/2366; 82/29; Antibodies; Autophagy - genetics; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Autophagy-Related Protein-1 Homolog; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Transformed; Diffusion Chambers, Culture; Forkhead Box Protein O1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Genes, Reporter; Hemorheology; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Luciferases - genetics; Luciferases - metabolism; Mechanotransduction, Cellular - genetics; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mutation; Original; original-article; Oxidation-Reduction; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Stress, Mechanical; Time Factors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Ubiquitin-Activating Enzymes - genetics; Ubiquitin-Activating Enzymes - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.193

Disturbed cell autophagy is found in various cardiovascular disease conditions. Biomechanical stimuli induced by laminar blood flow have important protective actions against the development of various vascular diseases. However, the impacts and underlying mechanisms of shear stress on the autophagic process in vascular endothelial cells (ECs) are not entirely understood. Here we investigated the impacts of shear stress on autophagy in human vascular ECs. We found that shear stress induced by laminar flow, but not that by oscillatory or low-magnitude flow, promoted autophagy. Time-course analysis and flow cessation experiments confirmed that this effect was not a transient adaptive stress response but appeared to be a sustained physiological action. Flow had no effect on the mammalian target of rapamycin-ULK pathway, whereas it significantly upregulated Sirt1 expression. Inhibition of Sirt1 blunted shear stress-induced autophagy. Overexpression of wild-type Sirt1, but not the deacetylase-dead mutant, was sufficient to induce autophagy in ECs. Using both of gain- and loss-of-function experiments, we showed that Sirt1-dependent activation of FoxO1 was critical in mediating shear stress-induced autophagy. Shear stress also induced deacetylation of Atg5 and Atg7. Moreover, shear stress-induced Sirt1 expression and autophagy were redox dependent, whereas Sirt1 might act as a redox-sensitive transducer mediating reactive oxygen species-elicited autophagy. Functionally, we demonstrated that flow-conditioned cells are more resistant to oxidant-induced cell injury, and this cytoprotective effect was abolished after inhibition of autophagy. In summary, these results suggest that Sirt1-mediated autophagy in ECs may be a novel mechanism by which laminar flow produces its vascular-protective actions.