The Effect And Underlying Mechanisms Of LCZ696 On Inhibiting Transverse Aortic Constriction Induced Cardiac Hypertrophy

Background: Cardiac hypertrophy is a maladaptive response to many pressure-overload diseases,such as hypertension,valvular heart disease.It eventually leads to heart failure,arrhythmias or even sudden death.It is reported that lymphatic vessels play an important role in the pathogenesis of several diseases and an increased number of lymphatic vessels is found in hypertrophic hearts.LCZ696,composed of the neprilysin inhibitor sacbitril and the angiotensin II type 1 receptor blocker valsartan,reduces cardiac hypertrophy and attenuates heart failure.However,whether LCZ696’s cardioprotection is associated with the change of cardiac lymphatic vessels remains unclear.Object: This study was aimed to explore whether LCZ696 has effects on cardiac hypertrophy and its possible mechanisms in transverse aortic constriction(TAC).Methods: A 27-gauge needle was tied on the aorta between the innominate and left carotid arteries to create a 70% aortic stenosis.Second day after the surgery,mice were randomly assigned to 3 groups,which were the sham,TAC,and TAC+ LCZ696 groups.To test whether LCZ696 could inhibit cardiac hypertrophy,we treated the surviving mice with either saline(sham group,TAC group)or LCZ696 at 60 mg/kg/day(TAC+ LCZ696 group)from the second day after surgery.Four weeks later,echocardiography was conducted to evaluate the cardiac function.Hematoxylin and eosin(HE)staining and Masson trichrome staining was carried out to assess the cardiomyocyte cross-sectional areas and the degree of cardiac fibrosis respectively.By q RT-PCR,we detected the expression of ANP and BNP in cardiac tissue.Moreover,the myocardial lymphatics and the levels of lymphangiogenic regulators were detected by immunohistochemistry analysis and western blots.Results: In this study,a significant increase in cardiac cross-sectional areas,myocardial fibrosis and hypertrophic markers were observed in TAC group,while all of these were found decreased in TAC+ LCZ696 group.After LCZ696 treatment,the cardiac function were improved,marked by the increased value of ejection fraction(%EF)(38.17±8.22% to 48.27±4.35%,P<0.05).From HE staining,we found that the heart size was enlarged in TAC group,while it was reduced in TAC+ LCZ696 group.From the results of Masson trichrome staining,we demonstrated that the extent of cardiac fibrosis was heightened by TAC,were attenuated by LCZ696 treatment.What’s more,the expression of ANP and BNP was detected increased in TAC group,while decreased in TAC+LCZ696 group.In addition,the cardiac lymphatic vessels and the levels of lymphangiogenic regulators were evaluated by immunohistochemistry and western blots.From the evaluation mentioned above,we found the attenuation of cardiac hypertrophy by LCZ696 was associated with the inhibition of cardiac lymphangiogenesis.Conclusion: LCZ696 ameliorates cardiac hypertrophy and relieves cardiac dysfunction in mice with TAC by inhibiting cardiac lymphangiogenesis.