Protective effect and mechanism of LCZ696 on diabetic cardiomyopathy rats / 西安交通大学学报(医学版)

ABSTRACT

【Objective】 To investigate the possible mechanism of sacubitril valsartan sodium (LCZ696) and valsartan in protecting rat cardiomyocytes under diabetic cardiomyopathy (DCM) by observing their effects on CGRP, TGF-β1/Smad7, caspase-3/Bcl-2 and Fas/FasL signaling pathways. 【Methods】 The diabetic model was made by the method of high glucose and high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Two rats were killed at the 4th, 6th and 8th week, respectively, to observe the myocardial structure. The myocardial structure of the rats changed at the 8th week, which was regarded as the success construction of diabetic cardiomyopathy model. The rats were randomly divided into four groups control+alcohol group, DCM+alcohol group, DCM+valsartan (DCM+VST) group, and DCM+LCZ696 (DCM+SVST) group. After that, equivalently intense alcohol was given to control+alcohol group and DCM+alcohol group, and 30 mg/(kg·d) valsartan was given to DCM+VST group, and 60 mg/(kg·d) LZC696 given to DCM+SVST group. At the end of the experiment, HE and Masson staining were used to observe the changes of myocardial histopathology; TUNEL used to observe the changes of myocardial apoptosis; immunohistochemistry used to detect the expressions of TGF-β1/ Smad7 and CGRP protein, Western blotting used to detect the expressions of caspase-3, Bcl-2, and Fas/FasL protein. 【Results】 Compared with those in control+alcohol group, rats in DCM+alcohol group had significantly decreased cardiac LVEF and LVFS values (P<0.05); cardiomyocyte hypertrophy; malalignment; more obvious interstitial fibrosis; more myocyte apoptosis (P<0.05); increased TGF-β1, caspase-3, and Fas/FasL protein expressions; and decreased CGRP, Smad7, and Bcl-2 protein expressions (P<0.05). Compared with DCM+alcohol group, DCM+VST group and DCM+SVST group ended up with improved rat cardiac function indicators and pathological changes; decreased TGF-β1, caspase-3 and Fas/FasL protein expressions(P<0.05); and increased CGRP, Smad7 and Bcl-2 protein expressions (P<0.05); DCM+SVST group was even superior to DCM+VST group in these aspects(P<0.05). 【Conclusion】 LCZ696 can antagonize the heart injury of DCM more effectively than valsartan. It protects the myocardium by regulating TGF-β1/Smad7, caspase-3/Bcl-2, and Fas/FasL signaling pathways and upregulating CGRP content.