胰高血糖素样肽-1通过上调其受体改善肥胖小鼠的血管内皮功能障碍

Glucagon-like peptide-1 (GLP-1) plays an important role through the activation of GLP-1 receptor (GLP-1R) in the cardiovascular system. The expression of GLP-1R in vascular endothelium of obesity remains largely unknown. Preliminary data in this study demonstrated that GLP-1R expression and CREB expression and phosphorylation were reduced in the aortae of high fat diet-induced obese (DIO) mice. While, a highly selective dipeptidyl peptidase 4 inhibitor sitagliptin elevated the expression and phosphorylation of CREB and increased the expression of GLP-1R through increasing endogenous GLP-1. In DIO mouse aortae, endothelium-dependent relaxation was impaired and eNOS phosphorylation was decreased. Moreover, DIO mice exhibited the reduced UCP2 level, the decreased AMPK phosphorylation and the enhanced endoplasmic reticulum (ER) stress-related protein expression and/or phosphorylation. Furthermore, the levels of miRNA-762/miR-3064-5p which regulated UCP2 were increased in DIO mice. However, endogenous GLP-1 counteracted all the above pathological features. Based on these observations, we speculated that GLP-1 regulated GLP-1R through the activation of CREB pathway; GLP-1R activation inhibited miRNA-762/miRNA-3064-5p, resulting in the up-regulation of UCP2 and subsequent activation of AMPK; then AMPK restored eNOS activity through inhibiting ER stress. The present study aimed to elucidate the mechanisms of GLP-1R up-regulation and subsequent improvement of vascular endothelial function by GLP-1 in obesity.

胰高血糖素样肽-1（GLP-1）通过激活其受体（GLP-1R）在心血管系统发挥重要作用，关于GLP-1R在肥胖血管内皮中的表达情况尚不明确。预实验显示：高脂饮食诱导的肥胖小鼠（DIO）主动脉中GLP-1R表达降低，CREB表达及磷酸化水平减少，而sitagliptin通过增加内源性GLP-1恢复CREB表达和磷酸化、上调GLP-1R；DIO小鼠主动脉内皮依赖性舒张减弱、UCP2表达及AMPK和eNOS磷酸化下降、内质网应激相关蛋白表达或磷酸化增加、调控UCP2的miRNA-762/miR-3064-5p增加；GLP-1使这些现象得到反转。据此提出科学设想：GLP-1通过CREB反馈调节GLP-1R表达后，通过抑制miRNA-762/miR-3064-5p上调UCP2、激活AMPK抑制内质网应激，恢复eNOS活性。本项目将深入研究GLP-1上调GLP-1R及其改善肥胖血管内皮功能的分子机制。

血管内皮功能障碍由一氧化氮（NO）产生与释放量减少、活性氧（ROS）增加、NO生物利用度降低所导致。在糖尿病、肥胖及高血压等疾病则可发生血管内皮功能障碍。.胰高血糖素样肽-1（GLP-1）通过激活其受体（GLP-1R）在心血管系统发挥重要作用。我们的研究表明，高脂饮食诱导的肥胖小鼠（DIO）主动脉中GLP-1R表达降低，CREB表达及磷酸化水平减少，而sitagliptin通过增加内源性GLP-1恢复CREB表达和磷酸化、上调GLP-1R；DIO小鼠主动脉内皮依赖性舒张减弱、UCP2表达及AMPK和eNOS磷酸化下降、内质网应激相关蛋白表达或磷酸化增加、调控UCP2的miR-3064-5p增加；GLP-1使这些现象得到反转。进而得出结论：GLP-1通过CREB反馈调节GLP-1R表达后，通过抑制miR-3064-5p上调UCP2、激活AMPK抑制内质网应激，从而恢复eNOS活性。上述研究进一步揭示了肥胖时血管功能障碍的细胞机制以及GLP-1对肥胖相关的心血管疾病中血管内皮功能的保护性作用。本研究还为GLP-1抗糖尿病特性的机制提供了新见解，GLP-1通过激活自噬恢复肥胖小鼠胰岛葡萄糖刺激的胰岛素分泌；然而，关于GLP-1在肥胖中激活自噬的机制有待进一步研究。.此外，我们阐明了钩藤碱在改善自发性高血压大鼠血管内皮功能中的作用并探寻其机制。钩藤碱通过激活PI3K/Akt-eNOS信号通路改善高血压大鼠肾内动脉的内皮依赖的舒张功能。该研究更好地揭示了钩藤碱的药理学作用，为其在临床上的应用提供了新的依据。