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

Dawn Thompson; Nicola Morrice; Louise Grant; Samantha Le Sommer; Emma K Lees; Nimesh Mody; Heather M Wilson; Mirela Delibegovic

doi:10.1042/CS20171066

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

Dawn Thompson^* (Corresponding Author), Nicola Morrice, Louise Grant, Samantha Le Sommer, Emma K Lees, Nimesh Mody, Heather M Wilson, Mirela Delibegovic

^*Corresponding author for this work

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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 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 with 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 of CVD risk.

Original language	English
Pages (from-to)	2489-2501
Number of pages	13
Journal	Clinical Science
Volume	131
Issue number	20
Early online date	12 Sept 2017
DOIs	https://doi.org/10.1042/CS20171066
Publication status	Published - 1 Oct 2017

Bibliographical note

The authors wish to thank Professor Nicholas Tonks for providing the PTP1B inhibitor trodusquemine; Linda Robertson for her help with the aorta histology; Dr Fiona Grieg for tuition into aortic dissection and Dr James Hislop for critical reading of this manuscript. We also wish to thank the British Heart Foundation (PG/14/43/30889) for supporting this research

Keywords

protein tyrosine phosphatases
metabolic syndromes
atherosclerosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1042/CS20171066Licence: CC BY

Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation
© 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). https://creativecommons.org/licenses/by/4.0/
Final published version, 1.22 MBLicence: CC BY

Mirela Delibegovic
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Professor in Diabetes Physiology and Signalling
- School of Medicine, Medical Sciences & Nutrition, Cardiometabolic Disease
- Institute of Medical Sciences
Person: Academic
Dawn Thompson
Person: Academic
Heather Wilson
Person: Academic

Cite this

Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis. / Thompson, Dawn (Corresponding Author); Morrice, Nicola; Grant, Louise et al.
In: Clinical Science, Vol. 131, No. 20, 01.10.2017, p. 2489-2501.

Research output: Contribution to journal › Article › peer-review

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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 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 with 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 of CVD risk.",

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note = "The authors wish to thank Professor Nicholas Tonks for providing the PTP1B inhibitor trodusquemine; Linda Robertson for her help with the aorta histology; Dr Fiona Grieg for tuition into aortic dissection and Dr James Hislop for critical reading of this manuscript. We also wish to thank the British Heart Foundation (PG/14/43/30889) for supporting this research",

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AB - 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 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 with 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 of CVD risk.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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Mirela Delibegovic

Dawn Thompson

Heather Wilson

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