| Background:At present,THP is widely used in the treatment of solid malignant tumors and hematological tumors,but it is accompanied by a variety of serious toxic and side effects,among which cardiotoxicity is most obvious.The mechanism of cardiotoxicity induced by THP may be related to oxidative stress injury and its related molecular pathways.At present,the most effective way to prevent cardiotoxicity caused by anthracyclines is the application of cardiovascular protection drugs.TRX is a derivative of the flavonoid rutin,which can change capillary permeability and has various pharmacological effects such as anti-inflammatory,anti-oxidation and anti-allergy.In this study,THP was used to replicate the rat model of chronic myocardial injury,and the protective effect of TRX on myocardial injury induced by THP and its related molecular mechanisms were explored.Objective:In this study,THP(3mg/kg,6w)was injected into the tail vein to replicate the rat model of chronic myocardial injury.The general state and body weight changes,electrocardiogram changes,cardiac function parameters,and serum oxidation-related active substances were observed.Detection,serum myocardial enzyme detection,myocardial tissue morphological changes,AKT,P-AKT,Caspase family and related apoptotic proteins in myocardial tissue,to explore the protective effect of TRX on THP-induced chronic myocardial injury in rats and its molecular mechanism To provide a theoretical basis for clinical application of TRX to prevent and treat cardiotoxicity caused by THP.Methods:Healthy adult male Wistar rats weighing 160±20 g were used to replicate the rat model of chronic myocardial injury using THP.The experiment was divided into 6 groups: normal group(CON group),pirarubicin group(THP),pirarubicin.+ Dexrazoxane(THP+DZR),pirarubicin + troxerutin low dose group(THP+TL group),pirarubicin + troxerutin middle dose group(THP+TM group),pirarubicin + troxerutin high dose group(THP+TH group).In the 1~7w experiment,rats in each dose group of TRX were given different doses of TRX aqueous solution(25mg/kg,50mg/kg,100mg/kg)every day,and the other groups were treated with normal saline.On the 8th day of the experiment,except for the DZR group,30 mg/kg DZR was injected into the tail vein,and the TRX group was treated with different doses of TRX aqueous solution,and CON and THP were given physiological saline.After the above treatment,each group of rats was treated with 3 mg/kg THP for 6 weeks except 30 minutes after injection of the same volume of normal saline in the tail vein of the CON group.The changes of general state and body weight,cardiac coefficient,electrocardiogram,cardiac function parameters and myocardial histomorphology were observed.The changes of serum myocardial enzymes and related oxidative active substances were determined.Western blotting was used to detect AKT and P-AKT.Expression levels of the Caspase family and related apoptotic proteins.The results are as follows:1.Continuous 6w tail vein injection of THP can induce an increase in cardiac coefficient in rats,a significant decrease in heart rate,a prolonged QT interval,a decrease in QRS complex voltage,an increase in LVEDP,a decrease in LVSP,±dp/dtmax,and LDH in serum.The levels of CKMB,cTn-T and BNP were elevated.The myocardial fibers produced by microscopic examination showed irregular arrangement of myocardial fibers,edema of myocardial cells and widening of the gap.Cytoplasmic lysis in the cytosol produces vacuolar degeneration and inflammatory cell infiltration.Prevention of TRX can significantly improve the above indicators,suggesting that troxerutin has a protective effect on THP-induced chronic myocardial injury in rats.2.troxerutin can improve the serum SOD activity and increase the content of MDA in rats induced by pirarubicin,and increase the expression of Pro-Caspase-9,Pro-Caspase-3 and Bcl-2.Reduce the expression of Cleaved Caspase-3 and Bax protein.It is indicated that the protective effect of troxerutin on chronic myocardial injury induced by pirarubicin is achieved by inhibiting oxidative stress and regulating Caspase signaling pathway.3.The effect of each dose of troxerutin on P-AKT is quite different.The low dose of troxerutin has no effect on P-AKT,and the middle dose of troxerutin can increase the expression level of P-AKT.High-dose rutin can reduce the expression of P-AKT.Regardless of the effect of low,medium and high doses of troxerutin on P-AKT expression,it did not affect downstream Pro-Caspase 9,Pro-Caspase-3,Cleaved Caspase-3,and Bcl-2 and Bax apoptosis.Protein expression,that is,the regulation of the Caspase signaling pathway by troxerutin is still present.It is suggested that the protective effect of troxerutin on chronic myocardial injury induced by THP may be achieved by regulating apoptotic factors in Caspase signaling pathway,and has nothing to do with P-AKT.The conclusion are as follows:1.troxerutin has a protective effect on chronic myocardial damage caused by pirarubicin.2.The protective effect of troxerutin on chronic myocardial injury induced by pirarubicin is achieved by inhibiting oxidative stress and regulating Caspase signaling pathway.3.The protective effect of troxerutin on Caspase signaling pathway in the treatment of chronic myocardial injury induced by THP was not associated with P-AKT. |
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