Herren David J, Norman J Blake, Anderson Ruchi, Tremblay Michel L, Huby Anne-Cecile, Belin de Chantemèle Eric J
Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA, United States of America.
Goodman Cancer Center and Department of Biochemistry, McGill University, Montreal, QC, Canada.
PLoS One. 2015 May 14;10(5):e0126866. doi: 10.1371/journal.pone.0126866. eCollection 2015.
Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM) was induced in wild-type (WT) and PTP1B-deficient mice (KO) with streptozotocin (STZ) injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384 ± 20 vs. Ko: 432 ± 29 mg/dL), cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice.
蛋白酪氨酸磷酸酶1B（PTP1B）使受体酪氨酸激酶去磷酸化，并在胰岛素信号通路中起分子制动器的作用。代谢功能障碍的情况下PTP1B会增加，而PTP1B缺失则通过增强胰岛素信号来预防代谢紊乱。尽管血管胰岛素信号有助于控制葡萄糖代谢，但关于PTP1B在调节内皮功能中的直接作用却知之甚少。我们推测，代谢功能障碍会增加内皮细胞中PTP1B的表达，而PTP1B缺失可在胰岛素分泌减少的情况下预防内皮功能障碍。通过注射链脲佐菌素（STZ）在野生型（WT）和PTP1B缺陷型小鼠（KO）中诱导出I型糖尿病（T1DM）。T1DM 28天后，KO小鼠的体重和血浆胰岛素水平下降程度与WT小鼠相似，血糖（WT：384±20 vs. Ko：432±29 mg/dL）、胆固醇和甘油三酯升高程度也与WT小鼠相当。T1DM增加了小鼠主动脉中PTP1B的表达，并损害了内皮细胞依赖一氧化氮的舒张功能。PTP1B缺失不影响T1DM小鼠的基线内皮功能，但保留了内皮依赖性舒张功能。用L-NAME抑制一氧化氮合酶可消除对照小鼠和T1DM WT小鼠的内皮舒张功能，而在T1DM KO小鼠中则需要L-NAME和环氧化酶抑制剂吲哚美辛才能消除内皮舒张功能。PTP1B缺失分别增加了T1DM小鼠主动脉和血浆中COX-2的表达及前列环素I2（PGI2）的水平。同时，在原代人主动脉内皮细胞中，模拟糖尿病状态会增加PTP1B的表达，敲低PTP1B会增加COX-2的表达，但不会增加COX-1的表达。综上所述，这些数据表明，在T1DM小鼠中，PTP1B缺失通过增加COX-2介导的血管舒张剂前列腺素PGI2的释放来补偿一氧化氮生物利用度的降低，从而保护内皮功能。
