The Protective Effect Of STV-Na And Its Analogs On Cardiotoxicity Induced By Doxorubicin

Objective1)To explore the protective effects of STV-Na and its analogs on cardiotoxicity induced by Dox;2)and explore its molecular mechanism.Research contents1.Evaluation of the protective effect of STV-Na on Dox-induced cardiotoxicity On zebrafish embryos,Dox-induced Tg[myl:EGFP]transgenic embryos were used to construct an embryonic cardiotoxicity model,and combined with STV-Na treatment.The overall survival rate was evaluated to obtain LC₅₀ values.The cardiac function of the embryo was further evaluated,and the embryonic heart rate（HR）,ventricular contraction fraction（FS）,ventricular volume（CV）,and stroke volume（CO）were used as indicators.In mice,a cardiotoxicity model was constructed by multiple intraperitoneal injections of Dox and treated with STV-Na.At the end of the experiment,the mice were anesthetized and the heart position was ultrasoundd using a small animal ultrasound system to evaluate ejection fraction（EF）,left ventricular contraction fraction（FS）,heart rate（HR）,and cardiac output（CO）.The content of CK,CK-MB and LDH in plasma was determined by ELISA.2.Evaluation of the protective effect of STV-Na analogs on Dox-induced cardiotoxicityFirst,a compound having no significant toxicity was selected by evaluating the embryo toxicity of the analogs itself.Then it was combined with Dox to treat the embryo,and the overall toxicity protection of the analogs was evaluated by the survival rate;further,the embryonic heart function was evaluated by quantitative method,and the analogs with significant cardioprotective activity was selected.3.Evaluation of Cardiotoxicity Induced by Sor and Sun by STV-Na and Its analogsEmbryo viability and cardiac function were evaluated using Sor and Sun-induced embryonic cardiotoxicity models in combination with STV-Na and its analogs.4.Molecular mechanism of STV-Na Protective effects on Dox-induced cardiotoxicityVRI was used to inhibit VEGF receptor,block VEGF signaling pathway,and combined with STV-Na treatment to evaluate cardiac function.The protective effect of STV-Na and KFH-08 on Dox-induced vascular injury was evaluated using the Tg[flk:EGFP]transgenic zebrafish line.On the embryo,q-PCR was used to detect the mRNA expression level of VEGF-related genes;in mouse heart tissue,WB method was used to detect VEGF signaling pathway（VEGF-A,VEGF-B,p-Erk/Erk,p-S6/S6）.The level of expression of the relevant protein.Results1.STV-Na significantly protects embryo damage and heart damage caused by Dox.LC₅₀0 increased from 51.56μM to 66.42μM,and significantly improved embryonic and mouse cardiac function.The results of ELISA showed that Dox significantly increased CK,CK-MB,and LDH,and CK,CK-MB,and LDH decreased significantly after treatment with STV-Na.2.In a series of new STV-Na analogs,the more active compound KFH-08was screened,which significantly improved the survival rate of the embryo.The LC50 value increased from 51.56μM to 75.23μM,and significantly improved embryonic heart function.3.STV-Na and analog KFH-08 have no improvement on embryo survival and cardiac function induced by Sor and Sun.4.After inhibition of the VEGF signaling pathway,STV-Na and its analogs have no protective effect on cardiotoxicity induced by Dox.RT-qPCR showed that STV-Na had no significant effect on mRNA expression of VEGF-related genes;however,at the protein level,STV-Na promoted phosphorylation of Erk and S6 downstream of VEGF.Conclusions1.STV-Na has a significant protective effect on cardiotoxicity caused by Dox.2.Screening for a novel STV analogs KFH-08 with significant myocardial protection.3.Myocardial protection of STV-Na and its analogs is dependent on the involvement of the VEGF/VEGFR signaling pathway.