Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia
Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia
复制标题
达沙替尼通过抑制高胆固醇血症小鼠模型中的胆固醇摄取来抑制动脉粥样硬化病变
DOI：
10.1016/j.jphs.2022.04.009
复制
发表时间：
2022
影响因子：
3.5
通讯作者：
Umemura Kazuo
中科院分区：
文献类型：
--
作者：
Takaba Masamitsu;Iwaki Takayuki;Arakawa Tomohiro;Ono Takaaki;Maekawa Yuichiro;Umemura Kazuo
尽管已知使用BCR-ABL 1酪氨酸激酶抑制剂（TKI）治疗慢性髓性白血病会导致血管不良事件（VAE），但达沙替尼给药期间VAE的频率并不高，动脉粥样硬化相关VAE也是如此。然而，其对动脉粥样硬化的作用仍存在争议。在这项研究中，我们的主要目的是研究达沙替尼如何影响动脉粥样硬化。Ldlr−/−/Apobec 1 −/−小鼠，这是非常容易发展动脉粥样硬化，给药达沙替尼。16周后，我们评估了他们的动脉粥样硬化病变。我们使用骨髓来源的巨噬细胞来研究氧化低密度脂蛋白（LDL）与DiI染料（DiI-oxLDL）复合物的摄取。进行RNA测序和定量逆转录聚合酶链反应（RT-qPCR），以探索达沙替尼对胆固醇代谢的潜在影响。与其他TKI不同，达沙替尼给药显著降低了动脉粥样硬化病变（P< 0.001和P =0.013）和DiI-oxLDL摄取（P< 0.001）。RNA测序和RT-qPCR表明，编码分拣蛋白（一种已知的LDL摄取调节剂）的Sort 1和Cd 36是达沙替尼的潜在靶点。总之，达沙替尼诱导LDL-C水平升高，但巨噬细胞中的oxLDL摄取受到抑制，导致动脉粥样硬化病变减少。这些结果进一步加深了我们对达沙替尼与其他TKI之间VAE差异的理解。
Although the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia is known to cause vascular adverse events (VAEs), the frequency of VAEs during dasatinib administration is not high, and the same holds for atherosclerosis-related VAEs. However, its effect on atherosclerosis remains controversial. In this study, our primary objective was to investigate how dasatinib affects atherosclerosis.Ldlr−/−/Apobec1−/−mice, which are highly prone to develop atherosclerosis, were administered dasatinib. After 16 weeks, we evaluated their atherosclerotic lesions. We used bone-marrow-derived macrophages to investigate the uptake of oxidized low-density lipoprotein (LDL) complexed with DiI dye (DiI-oxLDL). RNA sequencing and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed to explore the potential effects of dasatinib on cholesterol metabolism. Dasatinib administration significantly reduced atherosclerotic lesions (P< 0.001 andP =0.013) and DiI-oxLDL uptake (P< 0.001) unlike other TKIs. RNA sequencing and RT-qPCR suggested thatSort1, which encodes sortilin, a known regulator of LDL uptake, andCd36were potential targets of dasatinib. In conclusion, dasatinib induced elevated LDL-C levels, but oxLDL uptake in macrophages were suppressed, resulting in reducing atherosclerotic lesions. These results further our understanding of the differences in VAEs between dasatinib and other TKIs.