Apatinib Causes Hypertension via Drp1-Mediated Endothelial Mitochondrial Fission

Apatinib is a tyrosine kinase inhibitor used for targeted cancer therapy, but its cardiovascular toxicity, particularly hypertension, limits its clinical application. We observed significant mitochondrial fragmentation in endothelial cells after apatinib treatment. This study aims to investigate the role of endothelial mitochondrial fission mediated by Drp1 (dynamin-related protein 1) in apatinib-induced hypertension.

We established an apatinib-targeted gastric cancer-bearing nude mice model. Apatinib was also administered to human umbilical vein endothelial cells in vitro. Mitochondrial morphology changes in endothelial cells were examined. The role of Drp1 in this process was validated using various experimental methods. In addition, we explored the mechanisms by which March5 (membrane-associated RING-CH finger 5) regulates Drp1 ubiquitination and its role in endothelial dysfunction induced by apatinib.

In apatinib-treated human umbilical vein endothelial cells, mitochondrial fragmentation was evident, accompanied by a significant upregulation of Drp1 expression, leading to endothelial dysfunction. In tumor-bearing nude mice treated with apatinib, mitochondrial fragmentation in thoracic aortic endothelial cells increased, and Drp1 expression was significantly elevated. Drp1 knockdown or inhibition by Mdivi-1 (mitochondrial division inhibitor 1) alleviated endothelial dysfunction and hypertension. Interestingly, Mdivi-1 did not affect the antitumor efficacy of apatinib. Further mechanistic exploration revealed that apatinib partially inhibits the expression of March5, reducing Drp1 ubiquitination and degradation, thus promoting excessive mitochondrial fission.

This study demonstrates that apatinib induces endothelial dysfunction and hypertension by inhibiting March5 expression and reducing Drp1 ubiquitination. Inhibiting Drp1 alleviates excessive mitochondrial fission in endothelial cells, alleviating apatinib-induced endothelial dysfunction and hypertension, without compromising its antitumor effects.