Protective Mechanisim Of Valsartan On Myocardial Injury Induced By Doxorubicin

Objective: To establish an animal model of doxorubicin(Dox)induced myocardial injury in rats,and to investigate the protective effect and mechanism of valsartan(Vat)on myocardial injury induced by doxorubicin(Dox).Methods:Twenty-four clean-grade Sprague-Dawley rats were randomly divided into 4 groups: control group(intraperitoneal injection of normal saline + intragastric saline),Vat group [intraperitoneal injection of normal saline + gavage Vat 30 mg)/(kg·d)],doxorubicin group(peritoneal injection of Dox15 mg/kg),Dox+Vat group(peritoneal injection of Dox 15 mg/kg + gavage Vat 30 mg/(kg·d)],6 rats in each group.After 6 weeks,the serum levels of cardiac troponin I(cTnI)and brain natriuretic peptide(BNP)were determined by enzyme linked immunosorbent assay(ELISA).The serum superoxide dismutase(SOD)was determined by colorimetry,the level of angiotensin II(Ang II)in rat myocardium was detected by ELISA,observation of pathological changes of myocardial tissue by hematoxylin-eosin(HE)staining,and apoptotic rate of rat cardiomyocytes was detected by terminal deoxynucleotidyl transferase mediated nick end labeling(TUNEL).The expression of AT1 R and AT2 R ?reduced nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 4(Nox4)and apoptosis-related protein Bax and Bcl-2 were analyzed by Western blot.Results:Compared with the Con group,the levels of serum cTnI?BNP and cardiomyocyte apoptosis in the Dox group were significantly increased(P<0.05),the myocardial AngII content was significantly increased(P<0.05),and the serum SOD content was significantly decreased(P<0.05),myocardial fiber arrangement was disordered and the interstitial cells are severely edematous,and AT1 R expression was increased(P<0.05).Bax/Bcl-2 ratio was increased(p<0.05),and the expression of Nox4 was significantly increased(P<0.05).Compared with the Dox group,the serum cTnI and BNP levels and cardiomyocyte apoptosis rate were significantly decreased in the Dox+Vat group(P<0.05),serum SOD content was significantly increased(P<0.05),and the myocardial tissue pathological damage was significantly improved.The expression of AT1 R was decreased,while the expression of AT2 R was increased(P<0.05),the ratio of Bax/Bcl-2 was decreased(p<0.05)and the expression of Nox4 was decreased significantly(P<0.05).Conclusions: Vat has protective effect on Dox-induced myocardial injury in rats.The protective mechanism may be related to Vat blocking AT1 R directly,inhibiting oxidative stress response of myocardium and Vat feedback upregulating AT2 R expression,inhibiting Nox4 activity of myocardium,increasing antioxidant capacity of myocardium,and thus reducing apoptosis of myocardial cells.