Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B
Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B
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DOI：
10.1016/j.yjmcc.2012.03.003
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发表时间：
2012-06-01
影响因子：
5
通讯作者：
Richard, Vincent
中科院分区：
文献类型：
--
作者：
Gomez, Elodie;Vercauteren, Magali;Richard, Vincent
蛋白酪氨酸磷酸酶1B(PTP1B)调节酪氨酸激酶受体介导的反应，特别是对胰岛素敏感性有负面影响，因此PTP1B抑制剂(PTP1B)目前在糖尿病的背景下被评估。我们最近发现了PTP1bi的另一个重要靶点，即内皮保护。本研究旨在测试PTP1B活性降低是否有益于慢性心力衰竭(CHF)。我们评估了药物抑制2个月或PTP1B基因缺失(PTP1B(-/-))对CHF小鼠(心肌梗死后2个月)的影响。PTP1Bi和PTP1B缺乏减少了不良的左室重构，并改善了左心功能，表现为在相同的梗塞面积下，左室短轴缩短率和心输出量增加(超声心动图测量)，左室收缩末压增加，左室舒张末压降低。伴随着心肌纤维化减轻、心肌细胞肥大和心钠素的表达。在肠系膜小动脉节段进行的体外血管研究表明，无论是药物抑制还是基因缺失，血管内皮细胞功能都得到了恢复(即改善了NO依赖的血流介导的扩张，增加了eNOS的磷酸化)。与伴有胰岛素介导的肠系膜动脉扩张的野生型CHF相比，PTP1B(-/-)CHF患者的胰岛素敏感性也有所改善(通过正常血糖-高胰岛素钳试验进行评估)。因此，PTP1B的慢性药物抑制或基因缺失在不改变梗死面积的情况下改善了心脏功能障碍和心脏重塑。因此，该酶可能成为治疗CHF的新靶点。有心脏并发症的糖尿病患者可能通过两种不同的机制从抑制PTP1B中受益，减少糖尿病并发症和减少心力衰竭。(C)2012爱思唯尔有限公司。保留所有权利。
Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF).We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure. (C) 2012 Elsevier Ltd. All rights reserved.