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; Nicola Morrice; L  Grant; S. Le Sommer; K. Ziegler; P. Whitfield; Nimesh Mody; H.m. Wilson; Mirela 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
, Nicola Morrice
, L Grant
, S. Le Sommer
, K. Ziegler
, P. Whitfield
, Nimesh Mody
, H.m. Wilson
, Mirela Delibegovic

Division of Biomedical Sciences

Resultado de pesquisa: Article › revisão de pares

29 Citações (Scopus)

368 Transferências (Pure)

Resumo

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 hypothesised 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, AMPKα 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.

Idioma original	English
Revista	Molecular Metabolism
Data online antecipada	13 jun. 2017
DOIs	https://doi.org/10.1016/j.molmet.2017.06.003
Estado da publicação	E-pub ahead of print - 13 jun. 2017

ODS da ONU

Este resultado contribui para o(s) seguinte(s) Objetivo(s) de Desenvolvimento Sustentável

Good health and well being

Acesso ao documento

10.1016/j.molmet.2017.06.003Licença: CC BY

accepted manuscript
© 2017 The Authors. Published by Elsevier GmbH.
Accepted author manuscript, 4,57 MBLicença: CC BY
Thomson Mol Metabolism 2017
© 2017 The Authors. Published by Elsevier GmbH.
Proof, 4,55 MBLicença: CC BY
Thompson_et_al_Molecular_Metabolism_2017Final published version, 1 MBLicença: CC BY

http://linkinghub.elsevier.com/retrieve/pii/S2212877817303721

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Citar isto

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. Publicação online antecipada. https://doi.org/10.1016/j.molmet.2017.06.003

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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 hypothesised 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, AMPKα 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.",

author = "D. Thompson and Nicola Morrice and L Grant and \{Le Sommer\}, S. and K. Ziegler and P. Whitfield and Nimesh Mody and H.m. Wilson and Mirela Delibegovic",

year = "2017",

month = jun,

day = "13",

doi = "10.1016/j.molmet.2017.06.003",

language = "English",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier GmbH",

}

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. https://doi.org/10.1016/j.molmet.2017.06.003

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, Nicola

AU - Grant, L

AU - Le Sommer, S.

AU - Ziegler, K.

AU - Whitfield, P.

AU - Mody, Nimesh

AU - Wilson, H.m.

AU - Delibegovic, Mirela

PY - 2017/6/13

Y1 - 2017/6/13

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 hypothesised 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, AMPKα 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 hypothesised 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, AMPKα 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.

U2 - 10.1016/j.molmet.2017.06.003

DO - 10.1016/j.molmet.2017.06.003

M3 - Article

SN - 2212-8778

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -