胰高血糖素样肽-1保护高血压血管内皮功能的线粒体机制

Glucagon-like peptide-1 (GLP-1) plays anti-hypertensive effects by protecting vascular endothelial function in hypertension. The imbalance of mitochondrial fusion and fission induces cardiovascular diseases. However, the regulation of GLP-1 on the mitochondria of vascular endothelial cells in hypertension remains largely unknown. Preliminary data in this study demonstrated that angiotensin II (Ang II) induced the increase of blood pressure and impaired endothelium-dependent relaxation in the aortae from mice. Ang II resulted in the reduced phosphorylations of AMPK, Drp1, and eNOS and the decreased expression of Miro2. MK626, a dipeptidyl peptidase-4 inhibitor, inhibited such effects and improved endothelial function by increasing active GLP-1 level in plasma. Furthermore, the endothelial fucntion was also impaired by silencing Miro2. Importantly, Ang II did not induce endothelial dysfunction in Miro2 transgenic mice. Based on these observations, we speculate that Ang II leaded to the impairment of endothelial function by inducing the imbalance of mitohondrial dynamics; GLP-1 restored mitohondrial dynamics by up-regulating Miro2, thus ameliorating endothelial dysfunction. The current study aimed to elucidate the mitochondrial mechanism of the improvement of vascular endothelial function by GLP-1 in hypertension, thus providing new evidence for its clinical application.

胰高血糖素样肽-1（GLP-1）在高血压中通过保护血管内皮功能发挥降血压作用。线粒体融合和分裂失衡可诱发心血管疾病，然而关于GLP-1对高血压血管内皮细胞线粒体的调控尚不明确。本研究预实验显示：血管紧张素II（Ang II）诱导小鼠血压升高，引起主动脉内皮依赖的舒张功能受损，导致AMPK、Drp1和eNOS磷酸化水平降低、线粒体Miro2表达减少；二肽基肽酶-4抑制剂MK-626通过增加GLP-1翻转上述现象，改善血管内皮功能；敲低Miro2可引起血管内皮功能损伤，而Ang II未导致Miro2过表达小鼠发生血管内皮功能障碍。据此提出科学设想：Ang II可能通过引起线粒体功能障碍，导致血管内皮功能受损；而GLP-1上调血管内皮Miro2表达后，恢复线粒体动力学平衡，进而改善血管内皮功能。本项目将深入研究GLP-1保护高血压血管内皮功能的线粒体机制，为其在临床上的应用提供新的依据。

在糖尿病、高血压等疾病中常常并发血管内皮功能障碍，由一氧化氮（NO）生物利用度降低所导致，而血管内皮功能障碍又可进一步促进糖尿病和高血压的发生发展。.胰高血糖素样肽-1（GLP-1）在高血压中通过保护血管内皮功能发挥降血压作用。线粒体融合和分裂失衡可诱发心血管疾病，然而关于GLP-1对高血压时血管内皮细胞线粒体的调控尚不明确。我们的研究表明，血管紧张素II（Ang II）诱导小鼠血压升高，引起主动脉内皮依赖的舒张功能受损，导致AMPK、Drp1和eNOS磷酸化水平降低、线粒体Miro2表达减少；敲低Miro2可引起血管内皮功能损伤，而Ang II未导致Miro2过表达小鼠发生血管内皮功能障碍；二肽基肽酶-4抑制剂MK-626通过增加GLP-1调控小鼠主动脉lncRNAs表达谱、上调血管内皮Miro 2表达、恢复线粒体动力学平衡，进而改善血管内皮功能。本项目深入研究GLP-1保护高血压血管内皮功能的线粒体机制，为其在临床上的应用提供新的依据。.此外，我们阐明了丹酚酸B在糖尿病小鼠中通过调控BMP4-ROS环路改善血管内皮功能障碍。可溶性环氧化物水解酶抑制剂t-AUCB增加内源性环氧二十碳三烯酸，改善高血压大鼠肾内动脉和颌外动脉的内皮舒张功能，恢复肾血流量和下颌下腺的分泌，为高血压的防治提供参考。