Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

Abdelali Agouni; Simon  Tual-Chalot; Matthieu  Chalopin; Lucie  Duluc; Nimesh Mody; M. Carmen Martinez; Ramaroson Andriantsitohaina; Mirela Delibegovic

doi:10.1016/j.bcp.2014.10.008

Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

Abdelali Agouni, Simon Tual-Chalot, Matthieu Chalopin, Lucie Duluc, Nimesh Mody, M. Carmen Martinez, Ramaroson Andriantsitohaina, Mirela Delibegovic

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Abstract

Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B-/-) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity.
L-PTP1B-/- mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B-/- and control littermates; however, this was significantly lower in L-PTP1B-/- mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B-/- mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B−/− mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B−/− mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B−/− mice released higher levels of prostacylin, a vasorelaxant metabolite.
Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.

Original language	English
Pages (from-to)	607-617
Number of pages	11
Journal	Biochemical Pharmacology
Volume	92
Issue number	4
Early online date	30 Oct 2014
DOIs	https://doi.org/10.1016/j.bcp.2014.10.008
Publication status	Published - 15 Dec 2014

Keywords

PTP1B
insulin resistance
endothelial dysfunction
tyrosine phosphatase
eNOS

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Agouni_et_al_BiochemPharmacology_2014_PURE
NOTICE: this is the author’s version of a work that was accepted for publication in Biochemical Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochemical Pharmacology, VOL 92, ISSUE 4, (2014) DOI: 10.1016/j.bcp.2014.10.008
Accepted author manuscript, 1.14 MBLicence: Unspecified

http://authors.elsevier.com/a/1Q61R1Rct-f-r

Mirela Delibegovic
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Professor in Diabetes Physiology and Signalling
- Institute of Medical Sciences
Person: Academic

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@article{88c33cb320814a72981f468000d80270,

title = "Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction",

abstract = "Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B-/-) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity.L-PTP1B-/- mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B-/- and control littermates; however, this was significantly lower in L-PTP1B-/- mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B-/- mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B−/− mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B−/− mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B−/− mice released higher levels of prostacylin, a vasorelaxant metabolite. Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.",

keywords = "PTP1B, insulin resistance, endothelial dysfunction, tyrosine phosphatase, eNOS",

author = "Abdelali Agouni and Simon Tual-Chalot and Matthieu Chalopin and Lucie Duluc and Nimesh Mody and Martinez, {M. Carmen} and Ramaroson Andriantsitohaina and Mirela Delibegovic",

note = "Acknowledgments This work was supported by a Diabetes UK project grant to Dr M. Delibegovi{\'c} (BDARD08/0003597), Tenovus Scotland grant to Dr. M. Delibegovic and Dr. A. Agouni and travel grants from the Physiological Society and Company of Biologists to Dr. A. Agouni. Dr Delibegovic is also funded by an RCUK Fellowship, British Heart Foundation, EFSD/Lilly diabetes programme grant and the Royal Society. Dr Agouni is funded by the Royal Society and the Physiological Society. This work is supported by the INSERM and CHU of Angers. The authors are thankful to the functional imaging center of Angers (CIFAB) for the use of echocardiography.",

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doi = "10.1016/j.bcp.2014.10.008",

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T1 - Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

AU - Agouni, Abdelali

AU - Tual-Chalot, Simon

AU - Chalopin, Matthieu

AU - Duluc, Lucie

AU - Mody, Nimesh

AU - Martinez, M. Carmen

AU - Andriantsitohaina, Ramaroson

AU - Delibegovic, Mirela

N1 - Acknowledgments This work was supported by a Diabetes UK project grant to Dr M. Delibegović (BDARD08/0003597), Tenovus Scotland grant to Dr. M. Delibegovic and Dr. A. Agouni and travel grants from the Physiological Society and Company of Biologists to Dr. A. Agouni. Dr Delibegovic is also funded by an RCUK Fellowship, British Heart Foundation, EFSD/Lilly diabetes programme grant and the Royal Society. Dr Agouni is funded by the Royal Society and the Physiological Society. This work is supported by the INSERM and CHU of Angers. The authors are thankful to the functional imaging center of Angers (CIFAB) for the use of echocardiography.

PY - 2014/12/15

Y1 - 2014/12/15

N2 - Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B-/-) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity.L-PTP1B-/- mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B-/- and control littermates; however, this was significantly lower in L-PTP1B-/- mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B-/- mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B−/− mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B−/− mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B−/− mice released higher levels of prostacylin, a vasorelaxant metabolite. Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.

AB - Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B-/-) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity.L-PTP1B-/- mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B-/- and control littermates; however, this was significantly lower in L-PTP1B-/- mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B-/- mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B−/− mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B−/− mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B−/− mice released higher levels of prostacylin, a vasorelaxant metabolite. Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.

KW - PTP1B

KW - insulin resistance

KW - endothelial dysfunction

KW - tyrosine phosphatase

KW - eNOS

U2 - 10.1016/j.bcp.2014.10.008

DO - 10.1016/j.bcp.2014.10.008

M3 - Article

VL - 92

SP - 607

EP - 617

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 4

ER -

Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

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