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Objective:To observe the effects of sacubitril/valsartan (LCZ696) on viral replication and cardiomyocyte apoptosis in mice with coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) and to analyze the underlying mechanisms.Methods:Forty BALB/c mice were randomly divided into four groups with 10 in each group: Sham, Sham+ LCZ696, VMC, and VMC+ LCZ696 groups. VMC model was established by intraperitoneal injection of 0.1 ml of CVB3 with a concentration of 10 6 TCID 50/ml into BALB/c mice, while the sham intervention was an equal volume of saline. The day of virus injection was defined as day 0. LCZ696 was administered by gavage at a dose of 60 mg/kg every day for seven consecutive days starting from day 1. Mouse survival rates were calculated. Echocardiography was used to evaluate the cardiac function of mice. The level of creatine kinase-MB (CK-MB) was detected by ELISA. Western blot was used to detect the levels of inflammatory cytokines (IL-6, TNF-α), apoptosis-related proteins (caspase-3, cleaved-caspase-3, Bax, Bcl-2), CVB3 surface protein (VP-1) and p-AKT/AKT in the hearts of mice. CVB3 mRNA in mouse hearts was measured by PCR. Inflammatory cell infiltration and cell apoptosis in mouse hearts were observed by HE staining and TUNEL staining, respectively. Results:Compared with the Sham group, the mice in the VMC group had a decreased survival rate and impaired cardiac function ( P<0.05). The levels of CK-MB, IL-6, TNF-α, cleaved-caspase-3/caspase-3, Bax/Bcl-2, VP-1, and CVB3 mRNA in the hearts of VMC mice increased significantly ( P<0.05), accompanied by increased expression of AKT, decreased phosphorylation of AKT ( P<0.05) and increased cell apoptosis. LCZ696 reversed the above changes. It could increase the survival rate, improve the cardiac function ( P<0.05), decrease cardiac inflammation, cell apoptosis and viral replication ( P<0.05), and increase the phosphorylation of AKT ( P<0.05). LCZ696 had no significant effects on the survival rate, cardiac function, myocardial injury, cardiac inflammation, cell apoptosis, viral replication or the expression of PI3K/AKT signaling pathway-related proteins in normal mice. Conclusions:LCZ696 could significantly inhibit cardiomyocyte apoptosis and reduce CVB3 replication in the hearts of VMC mice by regulating the PI3K/AKT pathway, thereby improving mouse cardiac function and survival rate.
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Angiotensin receptor/neprilysin inhibitor (ARNI) is a novel combination drug that is a dual inhibitor of angiotensin receptor and neprilysin. In June 2021, the National Medical Products Administration approved ARNI for hypertension indications. This review provides an update of current literature on ARNI in elderly hypertension.
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【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.
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Chronic heart failure(CHF)is the performance of end-stage cardiovascular disease and the leading cause of death in recent years.With the rapid development of medical care,the mortality rate of heart failure is still high.This is one in the two major challenges in the cardiovascular field in the 21st century.The new drug LCZ696 is a dual inhibitors of angiotensin receptor blockers(ARB)and neprilysin(NEP),which may lead to new hope for patients with heart failure.In order to determine the efficacy and safety of LCZ696 in the treatment of heart failure,foreign countries have carried out some large-scale trials,such as PARAMOUT, PARADIGM,TITRATION and so on.The results of these studies reflected the superiority of LCZ696 compared with enalapril,valsartan and other drugs in the treatment of chronic heart failure.ARB/antiotensin converting enzyme inhibitors(ACEI)targets the angiotensin receptor to dilate blood vessels and inhibits the sympathetic nerve,but their effects on sodium withdrawal and diuresis are weak.The sacubitril in LCZ696 prevents natriuretic peptide from degrading,strengthens the natriuretic diuretic and further expansion of blood vessels.Thereby it improves water and sodium retention and cardiac function.It can play a better synergistic role combined with valsartan.
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In the 70s of last century, the treatment of chronic heart failure (CHF) mainly uses inotropic drugs, diuretic and vasodilators, which can improve the hemodynamic condition and have no change in mortality in patients. Since the end of 1980s, excessive activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system have demonstrated to play a key role in the pathophysiology of CHF. Blockade of these two systems can significantly reduce the mortality of CHF, which become a comerstone of the treatment of heart failure. Since 2010, three different types of drugs namely ivabradine, LCZ696 and a kind of traditional Chinese medicine have been shown confirmed the curative effects for heart failure, that means a new concept of CHF treatment, neurohormonal blockade/inducing and systematical regulation.
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Heart failure (HF) is a complex clinical syndrome, which is caused by cardiac structural abnormalities and dysfunction. It can lead to ventricular filling and impaired ejection capacity with high incidence and mortality . The constant activation of the rennin-angiotensin-aldosterone system (RAAS) plays an important role in the development of heart failure. Angiotensin angiotensin converting enzyme inhibitor (ACEI), angiotensin angiotensin receptor antagonist (ARB) and aldoste?rone receptor antagonist (MRA) had been confirmed to be with good therapeutic effects therefore played important roles in heart failure treatment strategy shown by large scale clinical trials. The first PARADIM-HF data published by European So?ciety of Cardiology in annual meeting on August 30, 2014 showed that LCZ696 can reduce cardiovascular mortality risk of HF patient by 20%when combining with beta blockers and MRA . It also reduced the number of hospitalizations of patients with chronic heart failure (CHF) by 21%. LCZ696, using its unique dual phase mode verified that the regulation of neuroen?docrine is the modern concept for the treatment of heart failure. LCZ696 lead to innovation and shed new light in traditional drug treatment for heart failure.