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.
LUNAM Université, Angers, France; INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Angers, France.
Biochem Pharmacol. 2014 Dec 15;92(4):607-17. doi: 10.1016/j.bcp.2014.10.008. Epub 2014 Oct 30.
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.
越来越多的证据表明，肝胰岛素抵抗足以促进心血管疾病的进展。我们之前已经表明，肝特异性蛋白酪氨酸磷酸酶 1B（PTP1B）缺乏可改善肝胰岛素敏感性和全身葡萄糖稳态。本研究的目的是研究肝特异性 PTP1B 缺乏（L-PTP1B-/-）对心脏和外周血管功能的影响，特别强调高脂肪饮食（HFD）诱导肥胖时的内皮功能。L-PTP1B-/- 小鼠表现出改善的葡萄糖和脂质稳态以及增加的胰岛素敏感性，而体重没有变化。HFD 喂养增加了 L-PTP1B-/- 和对照同窝仔鼠的收缩压（BP）；然而，L-PTP1B-/- 小鼠的血压明显较低。HFD 喂养仅增加了对照组小鼠的舒张压，而 L-PTP1B-/- 小鼠则完全受到保护。对左心室（LV）功能的分析表明，HFD 喂养降低了对照组动物的 LV 缩短分数，而 L-PTP1B-/- 小鼠则没有观察到。重要的是，HFD 喂养显著损害了对照组小鼠主动脉对乙酰胆碱的内皮依赖性血管舒张作用，而 L-PTP1B-/- 小鼠则完全受到保护。这与 eNOS 磷酸化的改变有关。使用 NS-398 选择性抑制 COX-2，仅降低了对照组小鼠对 5-HT 的收缩反应。HFD 喂养的对照组小鼠释放增强水平的前列腺素 E，一种血管收缩代谢物；而 HFD 喂养的 L-PTP1B-/- 小鼠则释放更高水平的前列腺素，一种血管舒张代谢物。我们的数据表明，肝 PTP1B 抑制可防止 HFD 诱导的内皮功能障碍，这突显了外周 PTP1B 抑制剂在降低肥胖相关心血管风险方面的潜力，除了其抗糖尿病作用之外。
