Study On Mechanism Of Oxaliplatin-induced Cardiotoxicity Based On The Morphology And Function Of Mithchondria

With the development of cardio-oncology in recent years,the cardiotoxicity of chemotherapy drugs have received more and more attention.Platinum-based chemotherapy drugs are effective for many malignant tumors.The adverse medicine reactions of third-generation platinum-based chemotherapy drug oxaliplatin are mainly in the nervous system and digestive system.But due to clinical reports of cardiac events caused by oxaliplatin,the potential cardiotoxicity of oxaliplatin cannot be ignored.Objective In this study,we investigated oxaliplatin-induced myocardial toxicity,to explore the relationship between myocardial injury and mitochondria-mediated endogenous apoptosis,and to observe the cardioprotective effects of vasorel.Methods32 ICR mice aged 8 weeks with the body weight of 20±2g were randomly divided into 4 groups: control group,low-does oxaliplatin group(L-OXL),high-does oxaliplatin group(H-OXL)and low-does oxaliplatin+vasorel group(L-OXL+Vasorel).Oxaliplatin was intraperitoneally injected with 4mg/kg as low-does and 8mg/kg as high-does,twice a week.We used gavage for vasorel,once a day.All drugs were continuously administered for 4 weeks.ECG and small animal heart ultrasonic testing were performed.CKMB,c Tn I and NT-pro BNP were determined.HE,Hoechst 33258 and Tunel stainning were used after tissue fixation and section.And we used q RT-PCR and Western Blot to observe Bcl-2,Bax,Cyt C,Caspase3,Caspase9 and PARP m RNA expression and protein expression changes.Results1.Changes in myocardial structure Cardiomyocytes with normal nucleus aligned neatly in control group.In the H-OXL group,some cardiomyocytes were irregularly arranged.2.Changes in serum myocardial injury markers Serum CKMB,c Tn I and NT-pro BNP levels were significantly higher in H-OXL group than those in control group and L-OXL group(P<0.05),and were significantly lower in L-OXL + Vasorel group than those in L-OXL group(P<0.05).3.ECG changes and echocardiographic changes There were no statistical significance changes in each group.LVEF and LVFS were significantly lower in H-OXL group than those in control group and L-OXL group(P<0.05),and were significantly higher in L-OXL + Vasorel group than in L-OXL group(P<0.05).4.Changes in mitochondrial structure and function Cardiac cell myofilament disordered,perinuclear space widened,mitochondria swollen,and ridges broken or disappeared in H-OXL group.ATP content in H-OXL group was significantly lower than in control group and L-OXL group(P<0.05),and was significantly higher in L-OXL + Vasorel group than in L-OXL group(P<0.05).5.Changes in mitochondrial induced apoptosis The ratio of Bcl-2/Bax was significantly lower in H-OXL group than in control group(P<0.05),and was significantly higher in L-OXL + Vasorel group than in L-OXL group(P<0.05).Cleaved-Caspase3,cleaved-Caspase9,cleaved-PARP and Cyt C were significantly higher in H-OXL group than those in control group and L-OXL group(P<0.05),and were significantly lower in L-OXL + Vasorel group than those in L-OXL group(P<0.05).Conclusion1.Oxaliplatin causes damage to myocardial mitochondrial structure in mice,leading to myocardial mitochondrial dysfunction.Mitochondrial-mediated endogenous apoptotic pathway activated,leading to myocardial cell apoptosis.2.High-dose of oxaliplatin can cause more severe damage to myocardial mitochondria,indicating that the cardiotoxicity of oxaliplatin is dose-dependent.3.Vasorel protects the heart by maintaining mitochondria in their normal structure and function and inhibiting mitochondrial-mediated endogenous apoptosis pathway.