硼替佐米的抗血栓作用依赖于转录因子 Kruppel 样因子 2（KLF2）。
The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2).
机构信息
Division of Hematology and Oncology, and Harrington Heart and Vascular Institute, Case Cardiovascular Research Institute, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH.
Harrington Heart and Vascular Institute, Case Cardiovascular Research Institute, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH.
出版信息
Blood. 2014 Jun 12;123(24):3828-31. doi: 10.1182/blood-2014-01-547448. Epub 2014 Apr 25.
Multiple myeloma confers a high risk for vascular thrombosis, a risk that is increased by treatment with immunomodulatory agents. Strikingly, inclusion of the proteasome inhibitor bortezomib reduces thrombotic risk, yet the molecular basis for this observation remains unknown. Here, we show that bortezomib prolongs thrombosis times in the carotid artery photochemical injury assay in normal mice. Cell-based studies show that bortezomib increases expression of the transcription factor Kruppel-like factor 2 (KLF2) in multiple cell types. Global postnatal overexpression of KLF2 (GL-K2-TG) increased time to thrombosis, and global postnatal deletion of KLF2 (GL-K2-KO) conferred an antiparallel effect. Finally, studies in GL-K2-KO mice showed that the thromboprotective effect of bortezomib is KLF2 dependent. These findings identify a transcriptional basis for the antithrombotic effects of bortezomib.
多发性骨髓瘤会增加血管血栓形成的风险，而使用免疫调节剂治疗会进一步增加这种风险。令人惊讶的是，蛋白酶体抑制剂硼替佐米的加入降低了血栓形成的风险，但这一观察结果的分子基础尚不清楚。在这里，我们表明硼替佐米延长了正常小鼠颈动脉光化学损伤模型中的血栓形成时间。基于细胞的研究表明，硼替佐米在多种细胞类型中增加了转录因子 Kruppel 样因子 2（KLF2）的表达。KLF2 的全局新生后过表达（GL-K2-TG）增加了血栓形成时间，而 KLF2 的全局新生后缺失（GL-K2-KO）则产生了相反的效果。最后，在 GL-K2-KO 小鼠中的研究表明，硼替佐米的抗血栓形成作用依赖于 KLF2。这些发现为硼替佐米的抗血栓形成作用确定了一个转录基础。
Zotero 插件