Inhibition of YAP by lenvatinib in endothelial cells increases blood pressure through ferroptosis

作者：Liang, Chen; Zhu, Di; Xia, Wei; Hong, Zi; Wang, Qiu-Shi; Sun, Yu; Yang, Yan-Chao; Han, Song-Qi; Tang, Liang-Liang; Lou, Jie; Wu, Ming-Ming; Zhang, Zhi-Ren^*

来源：Biochimica et Biophysica Acta - Molecular Basis of Disease, 2023, 1869(1): 166586.

DOI：10.1016/j.bbadis.2022.166586

• Lenvatinib
• Hypertension
• YAP
• Ferroptosis
• Endothelial dysfunction

Lenvatinib, a multitarget tyrosine kinase inhibitor (TKI), increases the incidence of severe hypertension and thus the incidence of cardiovascular complications. Inhibition of ferroptosis, a newly recognized type of cell death, alleviates endothelial dysfunction. Here, we report that lenvatinib-induced hypertension is associated with fer-roptosis of endothelial cells. RNA sequencing (RNA-seq) showed that lenvatinib led to ferroptosis of endothelial cells and that administration of mouse with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, dramatically ameliorated lenvatinib-induced hypertension and reversed lenvatinib-induced impairment of endothelium -dependent relaxation (EDR). Furthermore, lenvatinib significantly reduced glutathione peroxidase 4 (GPX4) expressions in the mouse aorta and human umbilical vein endothelial cells (HUVECs) and increased lipid per -oxidation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) levels in HUVECs. Immunofluo-rescence and Western blotting showed that lenvatinib significantly reduced Yes-associated protein (YAP) nuclear translocation but not cytoplasmic YAP expression in HUVECs. The data, generated from both in vivo and in vitro, showed that lenvatinib reduced total YAP (t-YAP) expression and increased the phosphorylation of YAP at both Ser127 and Ser397, without affecting YAP mRNA levels in HUVECs. XMU-MP-1 mediated YAP activation or YAP overexpression effectively attenuated the lenvatinib-induced decrease in GPX4 expression and increases in LDH release and MDA levels. In addition, overexpression of YAP in HUVECs ameliorated lenvatinib-induced decrease in the mRNA and protein levels of spermidine/spermine N (1)-acetyltransferase-1 (SAT1), heme oxygenase-1 (HO-1), and ferritin heavy chain 1 (FTH1). Taken together, our data suggest that lenvatinib-induced inhibi-tion of YAP led to ferroptosis of endothelial cells and subsequently resulted in vascular dysfunction and hypertension.

• 单位
  1; 哈尔滨医科大学