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, Samantha Le Sommer, K Ziegler, P Whitfield, N Mody, H M Wilson, M Delibegovic (Corresponding Author)

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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 languageEnglish
Pages (from-to)845-853
Number of pages9
JournalMolecular Metabolism
Volume6
Issue number8
Early online date13 Jun 2017
DOIs
Publication statusPublished - 1 Aug 2017

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
AMP-Activated Protein Kinases
Apolipoproteins E
Atherosclerotic Plaques
Interleukin-10
Atherosclerosis
Insulin Receptor
Macrophages
Cardiovascular Diseases
Adiposity
Knockout Mice
Insulin Resistance
Homeostasis
Anti-Inflammatory Agents
Body Weight
Phosphorylation
Atherogenic Diet
Glucose
Eicosanoids
Myeloid Cells

Keywords

  • PTP1B
  • Insulin resistance
  • Interleukin-10
  • AMPK
  • Atherosclerosis

Cite this

@article{335ac47990d647abb770068249fa0b68,
title = "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 = "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}, Samantha 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.",
year = "2017",
month = "8",
day = "1",
doi = "10.1016/j.molmet.2017.06.003",
language = "English",
volume = "6",
pages = "845--853",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
number = "8",

}

TY - JOUR

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, Samantha

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.

PY - 2017/8/1

Y1 - 2017/8/1

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

U2 - 10.1016/j.molmet.2017.06.003

DO - 10.1016/j.molmet.2017.06.003

M3 - Article

VL - 6

SP - 845

EP - 853

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 8

ER -