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

被引:21
作者
Agouni, Abdelali [1 ,2 ]
Tual-Chalot, Simon [3 ,4 ]
Chalopin, Matthieu [3 ,4 ]
Duluc, Lucie [1 ,3 ,4 ]
Mody, Nimesh
Martinez, M. Carmen [3 ,4 ,5 ]
Andriantsitohaina, Ramaroson [3 ,4 ,5 ]
Delibegovic, Mirela [1 ]
机构
[1] Univ Aberdeen, Sch Med Sci, Inst Med Sci, Aberdeen AB25 2ZD, Scotland
[2] Univ Surrey, Fac Hlth & Med Sci, Dept Biochem & Physiol, Guildford GU2 7XH, Surrey, England
[3] LUNAM Univ, Angers, France
[4] INSERM, U1063, Angers, France
[5] CHU Angers, Angers, France
关键词
PTP1B; Insulin resistance; Endothelial dysfunction; Tyrosine phosphatase; eNOS; NITRIC-OXIDE SYNTHASE; ENDOPLASMIC-RETICULUM STRESS; CONGESTIVE-HEART-FAILURE; INSULIN-RESISTANCE; CARDIAC DAMAGE; GENE DELETION; PROSTACYCLIN; ACTIVATION; MICE; INFLAMMATION;
D O I
10.1016/j.bcp.2014.10.008
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:607 / 617
页数:11
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