Studies On The Molecular And Cellular Mechanisms Of The Transition From VMC To DCM And The Effects Of Medicines

Studies on the Molecular and Cellular Mechanismsof the Transition from VMC to DCM andthe Effects of MedicinesABSTRACTBACKGROUND:Viral myocarditis (VMC) is an inflammatory disease of cardiac muscle which caused by viruses. It can be acute, subacute, or chronic, and there may be either focal or diffuse involvement of the myocardium. The most frequently implicated viruses are enteroviruses. The mortality of VMC in acute stage is about 11.2 %. Most of VMC patients had a good prognosis, about 13 percent of VMC processed dilated cardiomyopathy (DCM). Enteroviral genome were detected in 25-30 percent of DCM. The pathogenic mechanisms involved in the transition from VMC to DCM have been a challenging puzzle. It is suggested that persisted viral infection, immune-mediated injury and apoptosis possibly contributes to the evolution of ongoing heart disease. It was demonstrated that persisting replication-restricted enteroviral RNA could induce cardiomyopathic change. A recent study illustrated that Coxsackievirus B3 protease 2A cleaves cardiac cytoskeletal protein dystrophin. It was suggested molecular mechanism through which enteroviral infection contributes to the pathogenesis of acquired forms of DCM. CAR (Coxsackievirus-adenovirus receptor) is a common surface receptor for coxsackievirus and adenovirus. The expression of CAR are upregulated by viral infection, which in turn favored the invasion of virus. This positive feedback mechanism provides a new method to understand the onset of VMC and its treatment. The over-expression of endothelin system under pathologic conditions implicated in the procession of myocardial hypertrophy and ventricular remodeling in heart failure due to DCM. So to study the changes of CAR expression, hemodynamics andI?endothelin system are useful for us to understand the onset, sequelaand treatmellt of VMC.OBJECTIVE: to investigate the changes of myocardiumpathological changes, enteroviral RNA, viral receptor,hemodynamics and endothelin system in acute and chronic VMCmice which infected or re-infected with CVB3' to discuss thepossible mechanisms of the transition from VMC to DCM; to exPlorethe effects of Astragalus, perindopril and veraPamil to VMC mice.CONTENTS AND METHODSl. Three-week-old BALB/c mice were inoculated intraperitoneallywith CVB3 virus at the beginning of experimeflt to establish theVMC mice model. Meanwhile some VMC mice were treatCd withAstragalus, Perindopril and VeraPamil. Two weeks later, about halfof them were inoculated p.i. again. From 7ttr day to 5ttt month, themortality and pathological changes were observed. The myocardialenteroviral m, CARmRNA and ANPmRNA expression weredetected by using RT-PCR technique. The ANP concefltration wasdetermined by Radioimmuno assay.2. The changes of cardiac hemodynamics of VMC mice (single-infected and repetitive-infected) were recorded, in order to know theeffects of virus infection, re-infection and medicines for cardiachemodynamics.3. The changes of cardiac ETR Bmax and Kd in the hearts of VMCmice were measured by using Radio-ligand assay. RT-PCR assaycombined with autoradiograPhy were carried out to detect the InRNAexpression of ETAR and ETBR in the hearts of VMC mice. CardiacET-l concentrations were obtained by using Radioimmuno assay.Thus to study the effects of virus infection and repetitive infection forthe endothelin system in the hearts of VMC mice.RESULTSl 2l. Within the experimental period, mortality and pathological scoresin single-infected VMC mice model (M1) grouP were significanlyhigher than age-matched Normal (N) group (P<0.05-0.01 ). The meanbody weigh of M1 grouP was similar to age-matched N grOuP.Within 30 days postinfection, 9l.67%(ll/12) of Ml group wasdemonstrated positive fOr cardiac enteroviral RNA. There weretendency toward increasing of cardiac CAR mRNA, ANPmRNA.expression and AN'P concendation in M1 grouP after virusinoculation.In the course of experiment, mortality...