Researches on novel techniques of organ-selective gene therapy in thoracic surgery

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Heart failure, caused by various cardiac disorders such as dilated cardiomyopathy (DCM) and myocardial infarction, is the leading cause of death in developed countries, but no effective treatment except for the *ardic transplantation has been existed. Heart failure is pathophysiologically characterized by structural *modeling of the myocardium associated with myocyte hypertrophy, cell death and excess deposition of extracellular matrix, which causes functional impairment. Therefore, such a remodeling has emerged as a new therapeutic target of heart failure to improve the morbidity and mortality of the disease. Hepatocyte growth factor, originally cloned as a potent mitogen for mature hepatocytes, has angiogenic, anti-apoptotic and anti-fibrotic activities in various disease models, albeit not proved in the heart. In this research, we elucidated the role of HGF in the heart in the following points ; 1) We newly identified HGF as an endogenous cardioprotective factor, as HGF and c-Met/HG … More F receptor was rapidly upregulated after ischemia-reperfusion injury and HGF-administration significantly suppressed the pathological progression in ischemia-reperfusion injury. 2) In end-stage of DCM hamsters, the myocardial TGF-β1 levels, that is thought to be a crucial fibrogenic factor in chronic fibrotic disorders, increased, whereas the myocardial HGF levels significantly decreased. When the hamsters received daily administration with recombinant human HGF for 3 weeks, myocardial fibrotic area were significantly decreased, whereas the myocyte cross-sectional area was significantly increased. Moreover, the level of TGF-β1 and type I and III collagen mRNA were down-regulated and the progression of cardiac dysfunction was significantly inhibited. 3) When HGF gene was transfected into canine myocardium of rapid-pacing induced DCM, promoted the recovery in LV function, LV wall thickness, cell diameter, and angiogenesis and decreased the fibrosis and cardiomyocytes apoptosis. Our findings suggest that HGF or HGF gene therapy may be a novel therapeutic strategy for heart failure. Less