New therapeutic approach for heart failure using HB-EGF mediated signal transduction

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Dilated Cardiomyopathy is most important disease in cardiovascular field. In this research project, we focused on the identification of new therapeutic targets of heart failure. We established mice lacking growth factor HB-EGF. These mice suffered heart failure spontaneously and the pathological and physiological phenotypes are quite similar to these of human dilated cardiomyopahty. Using this animal model and human cases of cardiomyopaty, we examined the expression profile and screened out candidate genes which involved in the pathophysiology of heart failure. Among them we focused on the novel cardiac specific myosin light chain kinase named cardiac-MLCK This novel kinase was specifically expressed in heart and phsphorirates cardiac specific myosin light chain both in vivo and in vitro. Knock down of cardiac-MLCK in zebrafish caused sever impairment of cardiac development, suggesting its important role of cardiac development. Also in rat cultured cardiomyocytes, reducing expression of cardiac-MLCK caused impairment of cardiac sarcomere assembly. These data suggests that cardiac-MLCK is indispensable kinase of cardiac myosin light chain and essential for sarcomere assembly. Since MLCK expression was severely downregulated in cardiomyocyte in heart failure, reduced cardiac-MLCK may cause the insufficient sarcomere assembly resulting heart dysfunction. In fact the mutation of cardiac myosin light chain which is substrate of cardiac-MLCK is known to cause cardiomyopathy, indicating this substrate-kinase reaction is important for sarcomere assembly and its impairment causes cardiomyopathy. In conclusion we could successfully cloned out new therapeutic target of heart failure, cardiac-MLCK, using expression profiling of heart failure samples of model animal and human. Cardiac MLCK is potential target for cardiomyopathy. We are now screening other therapeutic targets using the same data base.