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A769662 inhibits insulin-stimulated akt activation in human macrovascular endothelial cells independent of AMP-activated protein kinase

Strembitska, Anastasiya; Mancini, Sarah J.; Gamwell, Jonathan M.; Palmer, Timothy M.; Baillie, George S.; Salt, Ian P.

Authors

Anastasiya Strembitska

Sarah J. Mancini

Jonathan M. Gamwell

George S. Baillie

Ian P. Salt



Abstract

Protein kinase B (Akt) is a key enzyme in the insulin signalling cascade, required for insulin-stimulated NO production in endothelial cells (ECs). Previous studies have suggested that AMP-activated protein kinase (AMPK) activation stimulates NO synthesis and enhances insulin-stimulated Akt activation, yet these studies have largely used indirect activators of AMPK. The effects of the allosteric AMPK activator A769662 on insulin signalling and endothelial function was therefore examined in cultured human macrovascular ECs. Surprisingly, A769662 inhibited insulin-stimulated NO synthesis and Akt phosphorylation in human ECs from umbilical veins (HUVECs) and aorta (HAECs). In contrast, the AMPK activators compound 991 and AICAR had no substantial inhibitory effect on insulin-stimulated Akt phosphorylation in ECs. Inhibition of AMPK with SBI-0206965 had no effect on the inhibition of insulin-stimulated Akt phosphorylation by A769662, suggesting the inhibitory action of A769662 is AMPK-independent. A769662 decreased IGF1-stimulated Akt phosphorylation yet had no effect on VEGF-stimulated Akt signalling in HUVECs, suggesting that A769662 attenuates early insulin/IGF1 signalling. The effects of A769662 on insulin-stimulated Akt phosphorylation were specific to human ECs, as no effect was observed in the human cancer cell lines HepG2 or HeLa, as well as in mouse embryonic fibroblasts (MEFs). A769662 inhibited insulin-stimulated Erk1/2 phosphorylation in HAECs and MEFs, an effect that was independent of AMPK in MEFs. Therefore, despite being a potent AMPK activator, A769662 has effects unlikely to be mediated by AMPK in human macrovascular ECs that reduce insulin sensitivity and eNOS activation.

Citation

Strembitska, A., Mancini, S. J., Gamwell, J. M., Palmer, T. M., Baillie, G. S., & Salt, I. P. (2018). A769662 inhibits insulin-stimulated akt activation in human macrovascular endothelial cells independent of AMP-activated protein kinase. International Journal of Molecular Sciences, 19(12), 3886. https://doi.org/10.3390/ijms19123886

Journal Article Type Article
Acceptance Date Dec 3, 2018
Online Publication Date Dec 5, 2018
Publication Date Dec 5, 2018
Deposit Date Dec 5, 2018
Publicly Available Date Dec 5, 2018
Electronic ISSN 1422-0067
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 19
Issue 12
Article Number 3886
Pages 3886
DOI https://doi.org/10.3390/ijms19123886
Keywords AMP-activated protein kinase; protein kinase B; Akt; insulin signalling; A769662; endothelial function
Public URL https://hull-repository.worktribe.com/output/1173131
Publisher URL https://www.mdpi.com/1422-0067/19/12/3886

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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/

Copyright Statement
©2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).





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