Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Atherosclerosis. 2014 Mar;233(1):64-71. doi: 10.1016/j.atherosclerosis.2013.12.032. Epub 2014 Jan 8.
We investigated the relationships among protein tyrosine phosphatase 1B (PTP1B), angiotensin II (Ang II), and insulin signaling in the presence of endothelial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rat aortas.
Aortas isolated from GK or control Wistar rats were examined in the presence or absence of Ang II with or without a selective antagonist of the Ang II type 1 (AT1) receptor or a PTP1B inhibitor to evaluate vascular functional and molecular mechanisms, such as insulin-induced relaxation, nitric oxide (NO) production, phosphorylation of insulin receptor substrate (IRS)-1, endothelial NO synthase (eNOS), and phosphorylation, and the subcellular localization of PTP1B. GK aortas exhibited reductions of: 1) insulin-induced relaxation, 2) NO production, 3) Ser(1177)-p-eNOS, and 4) Tyr(612)-p-IRS-1. Pre-incubation with a PTP1B inhibitor normalized these reductions. In Wistar aortas, the four above-mentioned parameters were reduced by Ang II, but were completely inhibited by co-treatment with the PTP1B inhibitor. The membrane expression of PTP1B was greater in GK than in Wistar aortas, and it was increased by Ang II in Wistar rats. The membrane PTP1B expression in the presence of insulin + Ang II was reduced by the PTP1B inhibitor or AT1-receptor antagonist.
These results suggest that the membrane PTP1B suppressed insulin-mediated aortic relaxation, and this was due to the Ang II-AT1-receptor signaling pathway. The inhibition of PTP1B warrants further investigation as a potential therapeutic target for endothelial dysfunction in type 2 diabetes.
本研究旨在探讨蛋白酪氨酸磷酸酶 1B（PTP1B）、血管紧张素 II（Ang II）与胰岛素信号通路之间的关系，研究对象为存在血管内皮功能障碍的 2 型糖尿病 Goto-Kakizaki（GK）大鼠主动脉。
本研究使用来自 GK 或对照 Wistar 大鼠的主动脉，在存在或不存在 Ang II 的情况下，评估血管功能和分子机制，如胰岛素诱导的舒张、一氧化氮（NO）产生、胰岛素受体底物（IRS）-1 的磷酸化、内皮型一氧化氮合酶（eNOS）和磷酸化以及 PTP1B 的亚细胞定位，以评估血管功能和分子机制。结果显示，与 Wistar 大鼠相比，GK 大鼠的主动脉表现出以下变化：1）胰岛素诱导的舒张作用减弱，2）NO 产生减少，3）Ser（1177）-p-eNOS 减少，4）Tyr（612）-p-IRS-1 减少。使用 PTP1B 抑制剂预处理可使这些变化恢复正常。在 Wistar 大鼠的主动脉中，上述四个参数在 Ang II 作用下减少，但在与 PTP1B 抑制剂共同处理后完全被抑制。与 Wistar 大鼠相比，GK 大鼠主动脉的膜 PTP1B 表达增加，Ang II 可进一步增加 Wistar 大鼠主动脉的膜 PTP1B 表达。胰岛素+Ang II 存在时，PTP1B 抑制剂或 AT1 受体拮抗剂可减少膜 PTP1B 表达。
这些结果表明，膜 PTP1B 抑制了胰岛素介导的主动脉舒张，这是由于 Ang II-AT1 受体信号通路所致。抑制 PTP1B 可能成为 2 型糖尿病内皮功能障碍的潜在治疗靶点，值得进一步研究。
