Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, PR China; Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, PR China.
Departments of Cardiology, Central Laboratory, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Harbin Medical University, PR China; Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, PR China.
Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166586. doi: 10.1016/j.bbadis.2022.166586. Epub 2022 Oct 29.
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 ferroptosis 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 peroxidation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) levels in HUVECs. Immunofluorescence 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 inhibition of YAP led to ferroptosis of endothelial cells and subsequently resulted in vascular dysfunction and hypertension.
仑伐替尼是一种多靶点酪氨酸激酶抑制剂（TKI），会增加严重高血压的发生率，从而增加心血管并发症的发生率。抑制铁死亡是一种新发现的细胞死亡方式，可减轻内皮功能障碍。在这里，我们报告仑伐替尼诱导的高血压与内皮细胞的铁死亡有关。RNA 测序（RNA-seq）显示，仑伐替尼导致内皮细胞发生铁死亡，而给予铁死亡抑制剂 Fer-1 的小鼠，其高血压显著改善，仑伐替尼诱导的内皮依赖性舒张功能障碍（EDR）也得到逆转。此外，仑伐替尼显著降低了小鼠主动脉和人脐静脉内皮细胞（HUVEC）中的谷胱甘肽过氧化物酶 4（GPX4）表达，并增加了 HUVEC 中的脂质过氧化、乳酸脱氢酶（LDH）释放和丙二醛（MDA）水平。免疫荧光和 Western blot 显示，仑伐替尼显著减少了 HUVEC 中的 Yes 相关蛋白（YAP）核转位，但不影响细胞质 YAP 的表达。来自体内和体外的数据表明，仑伐替尼降低了 HUVEC 中的总 YAP（t-YAP）表达，并增加了 YAP 在 Ser127 和 Ser397 处的磷酸化，而不影响 YAP 的 mRNA 水平。XMU-MP-1 介导的 YAP 激活或 YAP 过表达可有效减轻仑伐替尼引起的 GPX4 表达降低、LDH 释放增加和 MDA 水平升高。此外，在 HUVEC 中过表达 YAP 可改善仑伐替尼引起的 spermidine/spermine N（1）-乙酰基转移酶-1（SAT1）、血红素加氧酶-1（HO-1）和铁蛋白重链 1（FTH1）的 mRNA 和蛋白水平降低。总之，我们的数据表明，仑伐替尼诱导的 YAP 抑制导致内皮细胞铁死亡，进而导致血管功能障碍和高血压。
