A769662 Inhibits Insulin-Stimulated Akt Activation in Human Macrovascular Endothelial Cells Independent of AMP-Activated Protein Kinase
by
Anastasiya Strembitska 1, Sarah J. Mancini 1, Jonathan M. Gamwell 1,2, Timothy M. Palmer 1,3
, George S. Baillie 1 and Ian P. Salt 1,*
Anastasiya Strembitska 1, Sarah J. Mancini 1, Jonathan M. Gamwell 1,2, Timothy M. Palmer 1,3, George S. Baillie 1 and Ian P. Salt 1,*
1
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
2
Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
3
Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull HU6 7RX, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3886; https://doi.org/10.3390/ijms19123886
Received: 16 November 2018 / Accepted: 3 December 2018 / Published: 5 December 2018
(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)
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.
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Keywords:
AMP-activated protein kinase; protein kinase B; Akt; insulin signalling; A769662; endothelial function
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MDPI and ACS Style
Strembitska, A.; Mancini, S.J.; Gamwell, J.M.; Palmer, T.M.; Baillie, G.S.; Salt, I.P. A769662 Inhibits Insulin-Stimulated Akt Activation in Human Macrovascular Endothelial Cells Independent of AMP-Activated Protein Kinase. Int. J. Mol. Sci. 2018, 19, 3886.
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