Key result
Apatinib induces endothelial dysfunction and hypertension via Drp1-mediated mitochondrial fission, reversible by Drp1 inhibition.
Why the study?
Hypertension limits the clinical application of apatinib, and the role of Drp1-mediated mitochondrial fission in apatinib-induced endothelial dysfunction and hypertension was unclear.
Does Drp1 inhibition prevent apatinib-induced endothelial dysfunction and hypertension in preclinical models?
Does Drp1 inhibition prevent apatinib-induced endothelial dysfunction and hypertension in preclinical models?
Inhibiting Drp1-mediated mitochondrial fission alleviates apatinib-induced hypertension and endothelial dysfunction without reducing its antitumor efficacy.
Answers are grounded in this paper and cite their sources.
Apatinib may elevate hypertension risk via endothelial Drp1 activation; leaves open Drp1 inhibition as mitigation strategy in humans.
BACKGROUND: 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 Drp1 (dynamin-related protein 1)-mediated mitochondrial fission in apatinib-induced hypertension in endothelial cells. METHODS: 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. RESULTS: 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 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. CONCLUSIONS: 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.
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Si et al. (2026) studied Apatinib-induced hypertension. Apatinib was evaluated on Mitochondrial fragmentation, endothelial dysfunction, and hypertension. Apatinib induces endothelial dysfunction and hypertension via Drp1-mediated mitochondrial fission, which can be alleviated by Drp1 inhibition without compromising its antitumor efficacy.
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