| Malignant arrhythmia is one of major causes of death in patients with chronic heart failure. Molecular mechanisms of malignant arrhythmias in patients with chronic heart failure can be provided an important molecular target for prevention and treatment of cardiac sudden death.MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression,they are about 22 nucleotide noncoding small RNAs that inhibit transcription or translation by interacting with the 3’ untranslated region (3’UTR) of target mRNAs. Recent years, several studies have demonstrated the importance of miRNAs in the regulation of cardiac differentiation and disease. However, changes in the expression of miRNAs have been associated with cardiac development and several pathophysiological states including myocardial hypertrophy and heart failure.The changes in expression of miRNAs can lead to a variety of ion channel abnormal expressions, such as the sodium ion channels and calcium ion channels which are directly related to chronic heart failure. Most cardiac Na+ channels open transiently upon membrane depolarization and then are quickly inactivated. However, some channels remain active with carrying the so-called persistent or late Na+ current (INaL) during the action potential (AP) plateau.Chronic heart failure animal model prompt that INaL rise abnormally which makes action potential plateau significantly prolong. Finally induce early afterdepolarization and delayed afterdepolarization of failure myocardium, therefore lead to malignant arrhythmia.INaL is a kind of sodium channel current of voltage dependent type, it is mainly composed of a subunit protein which is encoded of SCN5A. Many articles reported, in heart failure cardiac muscle, the increasing of SCN5A gene expression lead to abnormal elevation of INaL.The targeting property of miRNAs determines the possibility of miRNAs act on cardiac ion channels related genes. Previous reports, a lot of miRNAs obviously up regulate or down regulate in failing heart, but reported results are inconsistent. In this rearch,we rearch whether miRNAs in patients’ plasma with malignant arrhythmia or the myocardium in dogs of chronic heart failure rise abnormally or not by observating the abnormal expression profile of miRNA in patients’ plasma with malignant arrhythmia or the myocardium in dogs of chronic heart failure. If some miRNAs rise abnormally, do the increased miRNAs play a role in the regulation and control to SCN5 A gene or others genes associated with heart failure? We carried out experiment research with these problems.Objectives:The role and mechanism research of microRNA in chronic heart failure malignant arrhythmia.Methods:Establishing the model of chronic heart failure (CHF model).The implanted pacer in dogs was set as the ventricular asynchronous pacing mode and programmed at 260 bpm±10 bpm for four weeks. By observing the signs, echocardiographic parameters of cardiac function and the cardiac morphological changes of dogs before and after the pacing, we evaluated the efficiency and safety of the method to establish the model of chronic heart failure model in dog using the rapid right ventricular pacing. Carry on the research of miRNA expression in myocardial tissue by the Danish Exiqon chip, and verify the result by qRT-PCR. Finally predict target genes by using three kinds of target gene prediction softwares.Results:After four weeks of rapid right ventricular pacing, all CHFdogs showed out of breath, a decreased activity, losing weight and serious cavity effusion. Echocardiographic study showed that the left ventricular ejection fraction was dropped from 61.5%±3.36% to 38.6%±2.88%. Gene chip, real-time fluorescent quantitative PCR and final target genes predicted results show that in the pathological conditions of chronic heart failure with malignant arrhythmia, miRNA-7,26,125 abnormally up regulate 1.45,5.71,1.56 times, respectively; miRNA-140 abnormally down regulate about 2 times. And SCN5A is their target gene.Conclusion:Under the condition of the pathology of chronic heart failure, miRNA-7,26,125 abnormally up regulate, miRNA-140 abnormally down regulate, And SCN5A in theory is their target gene.Moreover, in the process of the whole rearch, we also found and predicted other microRNAs and the corresponding target genes, which are associated with chronic heart failure. |
PDF Full Text Request