UNASSIGNED: Male C57BL/6 mice were randomly divided into three groups: control, crizotinib (40 mg ⋅ kg - 1 ⋅ d - 1 for four weeks), and crizotinib + sacubitril/valsartan (40 mg ⋅ kg - 1 ⋅ d - 1 /60 mg ⋅ kg - 1 ⋅ d - 1 for four weeks). Expression of genes in myocardial tissue were detected by transcriptomic sequencing, with verification of the differentially expressed genes (DEGs) using Real time-polymerase chain reaction (RT-PCR). Blood pressure (BP) and cardiac function of animals were measured using non-invasive monitoring and echocardiography approaches. Ventricular refractory period (RP), as well as the induction rate and score of ventricular arrhythmias (VAs) were detected by in vivo electrophysiology. Epicardial conductance was measured by mapping. Expression of Myh7 in myocardium was detected by western blot and RT-PCR.
UNASSIGNED: DEGs detected using transcriptomic sequencing included 10 up-regulated and 20 down-regulated genes. The first 5 DEGs identified were Myh7, Ngp, Lcn2, Ciart and Ptgds. Kyoto Encyclopedia of Genes and Genomes (KEGG) result indicated that Myh7 is involved in myocarditis, cardiomyopathy, and cardiac muscle contraction. Crizotinib treatment increased blood pressure, prolonged QTc interval, shortened ventricular RP, increased the incidence and score of right VAs, and increased Myh7 expression. Most of these responses were limited by sacubitril/valsartan.
UNASSIGNED: Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased Myh7 expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.
■雄性C57BL/6小鼠随机分为三组:对照组,克唑替尼(40mg·kg-1·d-1,持续四周),和克唑替尼+沙库巴曲/缬沙坦(40mg·kg-1·d-1/60mg·kg-1·d-1,持续四周)。用转录组测序法检测心肌组织中基因的表达,使用实时聚合酶链反应(RT-PCR)验证差异表达基因(DEGs)。使用非侵入性监测和超声心动图方法测量动物的血压(BP)和心脏功能。心室不应期(RP),以及通过体内电生理检测室性心律失常(VA)的诱导率和评分。通过作图测量心外膜电导。Westernblot和RT-PCR检测Myh7在心肌中的表达。
■使用转录组测序检测到的DEGs包括10个上调和20个下调的基因。确定的前5个DEG是Myh7,Ngp,Lcn2、Ciart和Ptgds。京都基因和基因组百科全书(KEGG)结果表明Myh7与心肌炎有关,心肌病,和心肌收缩。克唑替尼治疗血压升高,QTc间期延长,心室RP缩短,增加右侧VAs的发生率和评分,并增加Myh7表达。这些反应中的大多数受到沙库巴曲/缬沙坦的限制。
克唑替尼在小鼠模型中诱导了一系列心脏毒性副作用,而增加的Myh7表达代表了这种反应的生物标志物。沙库必曲/缬沙坦可以在很大程度上预防这些心血管毒性反应。