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.
authors.affiliation: University of Aberdeen, Institute of Medical Sciences, School of Medical Sciences, Foresterhill Health Campus, Aberdeen AB25 2ZD, United Kingdom; University of Surrey, Faculty of Health and Medical Sciences, Department of Biochemistry and Physiology, Guildford GU2 7XH, United Kingdom.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Agouni
authors.affiliation: LUNAM Université, Angers, France; INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Angers, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Tual-Chalot
authors.affiliation: LUNAM Université, Angers, France; INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Angers, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Chalopin
authors.affiliation: LUNAM Université, Angers, France; INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Angers, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Duluc
authors.affiliation: University of Aberdeen, Institute of Medical Sciences, School of Medical Sciences, Foresterhill Health Campus, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Nimesh
authors.initials: N
authors.lastname: Mody
authors.affiliation: LUNAM Université, Angers, France; INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Angers, France; CHU Angers, France.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Martinez
authors.affiliation: LUNAM Université, Angers, France; INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Angers, France; CHU Angers, France. Electronic address: ramaroson.andriantsitohaina@univ-angers.fr.
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.affiliation: University of Aberdeen, Institute of Medical Sciences, School of Medical Sciences, Foresterhill Health Campus, Aberdeen AB25 2ZD, United Kingdom. Electronic address: m.delibegovic@abdn.ac.uk.
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegović
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005947:Glucose
keywords: Endothelial dysfunction; Insulin resistance; PTP1B; Tyrosine phosphatase; eNOS