Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

D Thompson; N Morrice; L Grant; S. Le Sommer; K Ziegler; P Whitfield; N Mody; H M Wilson; M Delibegovic

doi:10.1016/j.molmet.2017.06.003

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

D Thompson^* (Corresponding Author), N Morrice, L Grant, S. Le Sommer, K Ziegler, P Whitfield, N Mody, H M Wilson, M Delibegovic^* (Corresponding Author)

^*Corresponding author for this work

University of the Highlands and Islands

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

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Abstract

Objective: 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) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.
Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed.
Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKa and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting.
Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE/ mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

Original language	English
Pages (from-to)	845-853
Number of pages	9
Journal	Molecular Metabolism
Volume	6
Issue number	8
Early online date	13 Jun 2017
DOIs	https://doi.org/10.1016/j.molmet.2017.06.003
Publication status	Published - 1 Aug 2017

Bibliographical note

Acknowledgements
The authors wish to thank 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

PTP1B
Insulin resistance
Interleukin-10
AMPK
Atherosclerosis

UN SDGs

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

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Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Final published version, 1.06 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
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
Person: Academic
Dawn Thompson
Person: Academic
Heather Wilson
Person: Academic

Cite this

Thompson, D., Morrice, N., Grant, L., Le Sommer, S., Ziegler, K., Whitfield, P., Mody, N., Wilson, H. M., & Delibegovic, M. (2017). Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway. Molecular Metabolism, 6(8), 845-853. https://doi.org/10.1016/j.molmet.2017.06.003

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway. / Thompson, D (Corresponding Author); Morrice, N; Grant, L et al.
In: Molecular Metabolism, Vol. 6, No. 8, 01.08.2017, p. 845-853.

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

Thompson, D, Morrice, N, Grant, L, Le Sommer, S, Ziegler, K, Whitfield, P, Mody, N , Wilson, HM & Delibegovic, M 2017, 'Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway', Molecular Metabolism, vol. 6, no. 8, pp. 845-853. https://doi.org/10.1016/j.molmet.2017.06.003

Thompson D, Morrice N, Grant L, Le Sommer S, Ziegler K, Whitfield P et al. Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway. Molecular Metabolism. 2017 Aug 1;6(8):845-853. Epub 2017 Jun 13. doi: 10.1016/j.molmet.2017.06.003

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abstract = "Objective: 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) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed.Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKa and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting.Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE/ mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk",

keywords = "PTP1B, Insulin resistance, Interleukin-10, AMPK, Atherosclerosis",

author = "D Thompson and N Morrice and L Grant and {Le Sommer}, S. and K Ziegler and P Whitfield and N Mody and Wilson, {H M} and M Delibegovic",

note = "Acknowledgements The authors wish to thank 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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T1 - Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

AU - Thompson, D

AU - Morrice, N

AU - Grant, L

AU - Le Sommer, S.

AU - Ziegler, K

AU - Whitfield, P

AU - Mody, N

AU - Wilson, H M

AU - Delibegovic, M

N1 - Acknowledgements The authors wish to thank 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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N2 - Objective: 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) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed.Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKa and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting.Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE/ mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

AB - Objective: 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) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed.Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE//LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKa and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting.Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE/ mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

KW - PTP1B

KW - Insulin resistance

KW - Interleukin-10

KW - AMPK

KW - Atherosclerosis

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DO - 10.1016/j.molmet.2017.06.003

M3 - Article

SN - 2212-8778

VL - 6

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JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 8

ER -

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE−/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

Abstract

Bibliographical note

Keywords

UN SDGs

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Mirela Delibegovic

Dawn Thompson

Heather Wilson

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