Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR −/− mouse model of atherosclerosis

Thompson, Dawn and Morrice, Nicola and Grant, Louise and Le Sommer, Samantha and Lees, Emma K. and Mody, Nimesh and Wilson, Heather M. and Delibegovic, Mirela (2017) Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR −/− mouse model of atherosclerosis. Clinical Science, 131 (20). pp. 2489-2501. ISSN 0143-5221

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Official URL: http://doi.org/10.1042/CS20171066

Abstract

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR-/- mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR-/- mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

Item Type: Article
Additional Information and Comments: This is the author's version of an article that was accepted for publication in Clinical Science. The final version is available at http://www.clinsci.org/content/131/20/2489 c 2017 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Faculty / Department: Faculty of Science > School of Health Sciences
Depositing User: Emma Lees
Date Deposited: 16 Feb 2018 14:13
Last Modified: 16 Feb 2018 14:13
URI: http://hira.hope.ac.uk/id/eprint/2377

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