Objective To investigate the intervention effect of sacubitril/valsartan(Sac/Val)on doxorubicin-induced heart failure(HF)in rabbits and its regulative effect on the transforming growth factor β1(TGF-β1)/SMAD family member 3(Smad3)/connective tissue growth factor(CTGF)signaling pathway.Methods Thirty-eight male New Zealand rabbits were subjected,and 8 of them were randomly assigned into a control group.The other 30 rabbits were injected with doxorubicin to establish a rabbit HF model,and finally,there were 6 rabbits in a model group,7 in a valsartan group,and 7 in a Sac/Val group.After 8 weeks of intervention,echocardiography[left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter(LVESD)],and myocardial histopathologic observation(HE staining,Masson staining)were performed,and collogen volume fraction(CVF)was calculated.The levels of N-terminal pro-B-type natriuretic peptide(NT-proBNP),soluble growth stimulation expressed gene 2(sST2),galectin-3(Gal-3)were detected.Activities of renin-angiotensin-aldosterone system(RAAS)and levels of atrial natriuretic peptide,B-type brain natriuretic peptide(BNP),cyclic guanosine monophosphate(cGMP)and protein kinase G(PKG)were measured.The expression of α-smooth muscle actin(α-SMA),typeⅠ collagen,TGF-β1,Smad3,recombinant SMAD family member 7(Smad7)and CTGF in the myocardial tissues were detected.Results Compared with the control group,the model group exhibited significantly lower LVEF and LVFS and decreased expression of Smad7,higher LVEDD and LVESD(P＜0.01).The CVF of each group was(7.15±0.82)％、(43.20±5.09)％、(29.53±4.05)％、(22.48±2.93)％.Valsartan and Sac/Val treatment resulted in obvious increases in LVEF and LVFS,up-regulation of Smad7,decreased in LVEDD,LVESD and CVF,reduced levels of NT-proBNP,sST2,Gal-3,AngⅡ,aldosterone,atrial natriuretic peptide,BNP,cGMP and PKG,and down-regulation of α-SMA,collagen I,TGF-β1,Smad3 and CTGF when compared with the model group(P＜0.01).Sac/Val treatment showed better effects in above indicators than simple valsartan treatment(P＜0.01).Conclusion Sac/Val can reduce myocardial fibrosis and improve cardiac function in doxorubicin-induced HF rabbits,which may be related to the dual inhibition of TGF-β1/Smad3/CTGF signaling pathway by upregulating atrial natriuretic peptide and BNP levels and blocking RAAS activation.

Objective To investigate the intervention effect of sacubitril/valsartan(Sac/Val)on doxorubicin-induced heart failure(HF)in rabbits and its regulative effect on the transforming growth factor β1(TGF-β1)/SMAD family member 3(Smad3)/connective tissue growth factor(CTGF)signaling pathway.Methods Thirty-eight male New Zealand rabbits were subjected,and 8 of them were randomly assigned into a control group.The other 30 rabbits were injected with doxorubicin to establish a rabbit HF model,and finally,there were 6 rabbits in a model group,7 in a valsartan group,and 7 in a Sac/Val group.After 8 weeks of intervention,echocardiography[left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter(LVESD)],and myocardial histopathologic observation(HE staining,Masson staining)were performed,and collogen volume fraction(CVF)was calculated.The levels of N-terminal pro-B-type natriuretic peptide(NT-proBNP),soluble growth stimulation expressed gene 2(sST2),galectin-3(Gal-3)were detected.Activities of renin-angiotensin-aldosterone system(RAAS)and levels of atrial natriuretic peptide,B-type brain natriuretic peptide(BNP),cyclic guanosine monophosphate(cGMP)and protein kinase G(PKG)were measured.The expression of α-smooth muscle actin(α-SMA),typeⅠ collagen,TGF-β1,Smad3,recombinant SMAD family member 7(Smad7)and CTGF in the myocardial tissues were detected.Results Compared with the control group,the model group exhibited significantly lower LVEF and LVFS and decreased expression of Smad7,higher LVEDD and LVESD(P＜0.01).The CVF of each group was(7.15±0.82)％、(43.20±5.09)％、(29.53±4.05)％、(22.48±2.93)％.Valsartan and Sac/Val treatment resulted in obvious increases in LVEF and LVFS,up-regulation of Smad7,decreased in LVEDD,LVESD and CVF,reduced levels of NT-proBNP,sST2,Gal-3,AngⅡ,aldosterone,atrial natriuretic peptide,BNP,cGMP and PKG,and down-regulation of α-SMA,collagen I,TGF-β1,Smad3 and CTGF when compared with the model group(P＜0.01).Sac/Val treatment showed better effects in above indicators than simple valsartan treatment(P＜0.01).Conclusion Sac/Val can reduce myocardial fibrosis and improve cardiac function in doxorubicin-induced HF rabbits,which may be related to the dual inhibition of TGF-β1/Smad3/CTGF signaling pathway by upregulating atrial natriuretic peptide and BNP levels and blocking RAAS activation.