Journal
INTERNATIONAL JOURNAL OF CARDIOLOGY
Volume 184, Issue -, Pages 86-95Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2015.01.065
Keywords
Shear stress; LOX-1; Autophagy; Inflammation
Categories
Funding
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, Washington, D [BX000282-05]
- National Natural Science Foundation of China [11332003, 61190123]
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Objectives: Shear stress, autophagy and LOX-1 are important players in atherogenesis. Direct impact of shear stress on autophagy development in endothelial cells and role of LOX-1 therein are undelineated. Methods and results: A parallel-plate flow chamber was used to vary shear stress (3 to 30 dyn/cm(2)), and determine autophagy in endothelial cells. We observed that low shear stress (3 dyn/cm2) enhanced autophagy (expression of LC3-II) 2-3 fold, and increasing shear stress (15 to 30 dyn/cm(2)) resulted in a gradual decline. Autophagy increased when cells were treated with an inflammatory stimulus lipopolysaccharide (LPS). LOX-1 expression paralleled autophagy development. The in vitro observations were confirmed in the in vivo setting by studying autophagy (LC3-II and Beclin-1) and LOX-1 expression in wild-type mice given LPS. Expression of both autophagy and LOX-1 was most pronounced in aorto-iliac bifurcation region where shear stress is lower compared with aortic arch, thoracic aorta and iliac artery. To define the role of LOX-1 in the development of autophagy, we studied LOX-1 knockout mice. These mice despite LPS administration exhibited less autophagy (vs. wild-typemice). Role of LOX-1 in the regulation of autophagy was further established with LOX-1 inhibition (siRNA transfection and use of antibody) or overexpression (cDNA transfection), which showed that LOX-1 knockdown reduced while LOX-1 overexpression enhanced LC3-II expression in endothelial cells. Conclusions: These observations suggest that low shear stress is a powerful regulator on autophagy, particularly in state of inflammation, and LOX-1 plays an important role in shear stress induced autophagy. Published by Elsevier Ireland Ltd.
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