Journal
BIOSCIENCE REPORTS
Volume 36, Issue -, Pages -Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BSR20160174
Keywords
AMP-activated protein kinase (AMPK); autophagy; endothelium; forkhead box protein O1 (FOXO1); glycogen synthase kinase 3 beta (GSK3 beta)
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Funding
- American Diabetes Association [7-11-MN-43]
- National Institute of Health National Institute of Diabetes and Digestive and Kidney Diseases Institute [NIH R01 DK067509-06, NIH R01 DK019514-34]
- NIH T32 Multidisciplinary Training in Cardiovascular Research grant [HL007224]
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High concentrations of glucose and palmitate increase endothelial cell inflammation and apoptosis, events that often precede atherogenesis. They may do so by decreasing basal autophagy and AMP-activated protein kinase (AMPK) activity, although the mechanisms by which this occurs are not clear. Decreased function of the lysosome, an organelle required for autophagy and AMPK, have been associated with hyperactivity of glycogen synthase kinase 3 beta (GSK3 beta). To determine whether GSK3 beta affects nutrient-induced changes in autophagy and AMPK activity, we used a primary human aortic endothelial cell (HAEC) model of type 2 diabetes that we had previously characterized with impaired AMPK activity and autophagy [Weikel et al. (2015) Am. J. Phys. Cell Physiol. 308, C249-C263]. Presently, we found that incubation of HAECs with excess nutrients (25 mM glucose and 0.4 mM palmitate) increased GSK3 beta activity and impaired lysosome acidification. Suppression of GSK3 beta in these cells by treatment with a chemical inhibitor or overexpression of kinase-dead GSK3 beta attenuated these lysosomal changes. Under control and excess nutrient conditions, knockdown of GSK3 beta increased autophagosome formation, forkhead box protein O1 (FOXO1) activity and AMPK signalling and decreased Akt signalling. Similar changes in autophagy, AMPK and Akt signalling were observed in aortas from mice treated with the GSK3 beta inhibitor CHIR 99021. Thus, increasing basal autophagy and AMPK activity by inhibiting GSK3 beta may be an effective strategy in the setting of hyperglycaemia and dyslipidaemia for restoring endothelial cell health and reducing atherogenesis.
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