Department of Cardiology, The No.4 Hospital of Jinan, 250031, Shandong, China.
Department of Cardiology, The No.4 Hospital of Jinan, 250031, Shandong, China.
Biochem Biophys Res Commun. 2019 Jan 22;508(4):1120-1125. doi: 10.1016/j.bbrc.2018.11.135. Epub 2018 Dec 12.
Mitochondrial dysregulation has been associated with vascular endothelial dysfunction and pathophysiological development of cardiovascular diseases. Lixisenatide is a drug approved by the US Food and Drug Administration for the treatment of type 2 diabetes (T2D). Little information regarding the effects of lixisenatide on mitochondrial function in endothelial cells has been reported before. In the current study, we found that treatment with lixisenatide significantly increased the expression of PGC-1α, a "molecular switch" of mitochondrial biogenesis in human umbilical vein endothelial cells (HUVECs). Lixisenatide treatment also promoted the expressions of NRF1 and TFAM, which are the target genes of PGC-1α and executors of mitochondrial biogenesis. Importantly, our results indicate that lixisenatide treatment promoted mitochondrial biogenesis by elevating the ratio of mitochondrial-to-nuclear DNA (mtDNA/nDNA), mitochondrial mass, cytochrome B expression, and citrate synthase activity in HUVECs. Correspondingly, we found that lixisenatide treatment led to a functional gain and improvement in mitochondria by increasing the mitochondrial respiration rate and ATP generation. Mechanistically, lixisenatide treatment induced the phosphorylation of CREB at Ser133. Blockage of CREB phosphorylation using its inhibitor H89 abolished the effects of lixisenatide on the activation of PGC-1α/NRF-1/TFAM as well as the increase in mtDNA/nDNA. These findings suggest that lixisenatide promoted mitochondrial biogenesis in endothelial cells through activating the PGC-1α signaling pathway, which is mediated by the transcriptional factor CREB.
线粒体功能失调与血管内皮功能障碍及心血管疾病的病理生理发展有关。利西那肽是一种经美国食品和药物管理局批准用于治疗 2 型糖尿病（T2D）的药物。以前很少有关于利西那肽对内皮细胞线粒体功能影响的报道。在本研究中，我们发现利西那肽处理显著增加了人脐静脉内皮细胞（HUVEC）中 PGC-1α的表达，PGC-1α是线粒体生物发生的“分子开关”。利西那肽处理还促进了 NRF1 和 TFAM 的表达，它们是 PGC-1α的靶基因，也是线粒体生物发生的执行者。重要的是，我们的结果表明，利西那肽通过提高 HUVEC 中线粒体与核 DNA（mtDNA/nDNA）、线粒体质量、细胞色素 B 表达和柠檬酸合酶活性的比值，促进了线粒体生物发生。相应地，我们发现利西那肽处理通过增加线粒体呼吸率和 ATP 生成，导致线粒体功能获得和改善。在机制上，利西那肽处理诱导 CREB 在 Ser133 处磷酸化。使用其抑制剂 H89 阻断 CREB 磷酸化，可消除利西那肽对 PGC-1α/NRF-1/TFAM 激活以及 mtDNA/nDNA 增加的作用。这些发现表明，利西那肽通过激活 PGC-1α 信号通路促进内皮细胞中线粒体生物发生，该通路由转录因子 CREB 介导。
