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

Dawn Thompson, Nicola Morrice, Louise Grant, Samantha Le Sommer, K Ziegler, Phillip Whitfield, Nimesh Mody, Heather Wilson, Mirela Delibegovic

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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 toaccelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulinreceptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulinresistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of theIR, 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 fedstandard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and mo-lecular, 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 ho-meostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. Thiswas associated with enhanced phosphorylation of aortic Akt, AMPKaand increased secretion of circulating anti-inflammatory cytokineinterleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect ofmyeloid-PTP1B targeting.

Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atheroscleroticplaque formation, under atherogenic conditions, in an ApoE/mouse model of atherosclerosis. Ourfindings suggest for thefirst time thatmacrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.
Original languageEnglish
Pages (from-to)845-853
JournalMolecular Metabolism
Volume6
Issue number8
DOIs
Publication statusPublished - Jun 2017

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Apolipoproteins E
Atherosclerotic Plaques
Interleukin-10
Atherosclerosis
Cardiovascular Diseases
Macrophages
Adiposity
Knockout Mice
Anti-Inflammatory Agents
Body Weight
Phosphorylation
Atherogenic Diet
Glucose
Eicosanoids
Myeloid Cells
Dinoprostone
Type 2 Diabetes Mellitus
Insulin Resistance
Homeostasis

Cite this

Thompson, Dawn ; Morrice, Nicola ; Grant, Louise ; Le Sommer, Samantha ; Ziegler, K ; Whitfield, Phillip ; Mody, Nimesh ; Wilson, Heather ; Delibegovic, Mirela. / Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKa pathway. In: Molecular Metabolism. 2017 ; Vol. 6, No. 8. pp. 845-853.
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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 toaccelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulinreceptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulinresistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of theIR, 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 fedstandard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and mo-lecular, 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 ho-meostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. Thiswas associated with enhanced phosphorylation of aortic Akt, AMPKaand increased secretion of circulating anti-inflammatory cytokineinterleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect ofmyeloid-PTP1B targeting.Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atheroscleroticplaque formation, under atherogenic conditions, in an ApoE/mouse model of atherosclerosis. Ourfindings suggest for thefirst time thatmacrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.",
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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/AMPKa pathway. / Thompson, Dawn; Morrice, Nicola; Grant, Louise; Le Sommer, Samantha; Ziegler, K; Whitfield, Phillip; Mody, Nimesh; Wilson, Heather ; Delibegovic, Mirela.

In: Molecular Metabolism, Vol. 6, No. 8, 06.2017, p. 845-853.

Research output: Contribution to journalArticle

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/AMPKa pathway

AU - Thompson, Dawn

AU - Morrice, Nicola

AU - Grant, Louise

AU - Le Sommer, Samantha

AU - Ziegler, K

AU - Whitfield, Phillip

AU - Mody, Nimesh

AU - Wilson, Heather

AU - Delibegovic, Mirela

PY - 2017/6

Y1 - 2017/6

N2 - Objective: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due toaccelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulinreceptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulinresistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of theIR, 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 fedstandard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and mo-lecular, 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 ho-meostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. Thiswas associated with enhanced phosphorylation of aortic Akt, AMPKaand increased secretion of circulating anti-inflammatory cytokineinterleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect ofmyeloid-PTP1B targeting.Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atheroscleroticplaque formation, under atherogenic conditions, in an ApoE/mouse model of atherosclerosis. Ourfindings suggest for thefirst time thatmacrophage 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 toaccelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulinreceptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulinresistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of theIR, 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 fedstandard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and mo-lecular, 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 ho-meostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. Thiswas associated with enhanced phosphorylation of aortic Akt, AMPKaand increased secretion of circulating anti-inflammatory cytokineinterleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect ofmyeloid-PTP1B targeting.Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atheroscleroticplaque formation, under atherogenic conditions, in an ApoE/mouse model of atherosclerosis. Ourfindings suggest for thefirst time thatmacrophage 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

VL - 6

SP - 845

EP - 853

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 8

ER -