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

Dawn Thompson, Nicola Morrice, Louise Grant, Emma K. Lees, Nimesh Mody, Heather Wilson, Mirela Delibegovic

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)2489-2501
JournalClinical Science
Volume131
Issue number20
DOIs
Publication statusPublished - 29 Sep 2017

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

Cite this

Thompson, Dawn ; Morrice, Nicola ; Grant, Louise ; Lees, Emma K. ; Mody, Nimesh ; Wilson, Heather ; Delibegovic, Mirela. / Pharamcological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in LDLR-/- mouse model of atherosclerosis. In: Clinical Science. 2017 ; Vol. 131, No. 20. pp. 2489-2501.
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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 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.",
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Pharamcological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in LDLR-/- mouse model of atherosclerosis. / Thompson, Dawn; Morrice, Nicola; Grant, Louise; Lees, Emma K.; Mody, Nimesh; Wilson, Heather ; Delibegovic, Mirela.

In: Clinical Science, Vol. 131, No. 20, 29.09.2017, p. 2489-2501.

Research output: Contribution to journalArticle

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AU - Morrice, Nicola

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AU - Lees, Emma K.

AU - Mody, Nimesh

AU - Wilson, Heather

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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 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.

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