Objective: Apatinib demonstrates significant antigastric cancer efficacy, but its hypertensive side effects frequently limit its clinical application. This study aimed to investigate the mitochondrial mechanism underlying apatinib induced dysfunction in HUVECs. Design and method: Based on the plasma drug concentration observed during apatinib treatment for gastric cancer, HUVECs were treated apatinib for forty eight hours. Mitochondria were labeled with Mito Tracker and observed using two photon confocal microscopy, while MitoSOX was measured. Western blot was performed to detect the expression of mitochondrial fission proteins Drp1 and Fis1, as well as the level of eNOS phosphorylation and NO in the culture medium. Subsequently, after knocking down Drp1 with siDrp1 RNA, mitochondrial morphology was observed, and MitoSOX was measured. Western blot was also used to examine the expression of Drp1 and Fis1, as well as eNOS phosphorylation and NO levels in the culture medium. Results: Apatinib significantly induced excessive mitochondrial fragmentation accompanied by substantial generation of mitochondrial ROS. This process was mediated by increased expression of Drp1 and Fis1. Knockdown of Drp1 improved excessive mitochondrial fragmentation and enhanced eNOS phosphorylation and NO production in HUVECs. Conclusions: Apatinib leads to dysfunction of HUVECs through Drp1 mediated excessive mitochondrial fission.
Si et al. (Fri,) studied this question.