Pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) 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

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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 languageEnglish
Pages (from-to)2489-2501
Number of pages13
JournalClinical Science
Volume131
Issue number20
Early online date12 Sep 2017
DOIs
Publication statusPublished - 29 Sep 2017

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Atherosclerotic Plaques
Atherosclerosis
Pharmacology
Insulin Receptor
Cardiovascular Diseases
AMP-Activated Protein Kinases
Chemokine CCL2
Adiposity
Type 2 Diabetes Mellitus
Weight Gain
Insulin Resistance
Triglycerides
Homeostasis
Cholesterol
Glucose
Mortality

Keywords

  • insulin
  • insulin resistance
  • insulin receptor
  • AMPK
  • atherosclerosis

Cite this

@article{e9dc3ac047a14f02bcec66716c56a8be,
title = "Pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis",
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.",
keywords = "insulin, insulin resistance, insulin receptor, AMPK, atherosclerosis",
author = "Dawn Thompson and Nicola Morrice and Louise Grant and {Le Sommer}, Samantha and Lees, {Emma K} and Nimesh Mody and Wilson, {Heather M} and Mirela Delibegovic",
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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language = "English",
volume = "131",
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TY - JOUR

T1 - Pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis

AU - Thompson, Dawn

AU - Morrice, Nicola

AU - Grant, Louise

AU - Le Sommer, Samantha

AU - Lees, Emma K

AU - Mody, Nimesh

AU - Wilson, Heather M

AU - Delibegovic, Mirela

N1 - 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

PY - 2017/9/29

Y1 - 2017/9/29

N2 - 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.

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.

KW - insulin

KW - insulin resistance

KW - insulin receptor

KW - AMPK

KW - atherosclerosis

U2 - 10.1042/CS20171066

DO - 10.1042/CS20171066

M3 - Article

VL - 131

SP - 2489

EP - 2501

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 20

ER -