Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway
Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway
复制标题
DOI：
10.2337/diabetes.51.1.168
复制
发表时间：
2002-01-01
期刊：
影响因子：
7.7
通讯作者：
Lembo, G
中科院分区：
文献类型：
--
作者：
Vecchione, C;Maffei, A;Lembo, G
最近的证据表明，除了对中枢神经系统的作用，瘦素可以通过涉及一氧化氮（NO）释放的局部机制来调节血管张力。在这项研究中，使用荧光探针直接测定NO，我们证明了在内皮细胞和血管中，瘦素能够刺激NO的释放。钙离子非依赖性酪氨酸激酶抑制剂erbstatin A可阻断瘦素对NO的作用，而钙离子去除或其他蛋白磷酸化抑制剂如染料木素（一种ATP依赖性酪氨酸激酶抑制剂）或渥曼青霉素和LY 294002（两种不同的磷脂酰肌醇[PI] 3-激酶抑制剂）则不影响瘦素对NO的作用。因此，瘦素诱导的主动脉环血管舒张仅被厄布他汀A消除。此外，免疫印迹研究显示，瘦素引起Akt磷酸化，在内皮细胞和血管中具有可比的时间过程。同样在这个实验系统中，瘦素的作用被厄布他汀A消除，而不是被其他抑制剂消除。最后，当用瘦素处理血管时，发现内皮NO合酶（eNOS）Ser（1177）磷酸化显著增加。总之，瘦素通过激活PI 3-激酶非依赖性Akt-eNOS磷酸化途径诱导NO产生。
Recent evidence suggests that besides its action on the central nervous system, leptin can modulate vascular tone through local mechanisms involving nitric oxide (NO) release. In this study, using a fluorescent probe for direct determination of NO, we demonstrated both in endothelial cells and in vessels that leptin is able to stimulate NO release. The effect of leptin on NO is abolished by erbstatin A, a Ca2+-independent tyrosine kinase inhibitor, whereas it is not influenced by calcium removal or by other protein phosphorylation inhibitors, such as genistein (an ATP-dependent tyrosine-kinase inhibitor) or wortmannin and LY294002 (two different phosphatidylinositol [PI] 3-kinase inhibitors). Accordingly, leptin-induced vasorelaxation in aortic rings was abolished only by erbstatin A. Furthermore, immuno-blotting studies revealed that leptin evokes Akt phosphorylation, with a comparable time course in both endothelial cells and vessels. Also in this experimental system, the effect of leptin was abolished by erbstatin A and not by other inhibitors. Finally, a considerable increase in endothelial NO synthase (eNOS) phosphorylation in Ser(1177) was found when vessels were treated with leptin. In conclusion, leptin induces NO production by activating a PI 3-kinase-independent Akt-eNOS phosphorylation pathway.