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

在发达国家，由各种心脏疾病如扩张型心肌病（DCM）和心肌梗死引起的心力衰竭是导致死亡的主要原因，但除心脏移植外，尚无有效的治疗方法。心力衰竭的病理生理学特征是与肌细胞肥大、细胞死亡和细胞外基质过度沉积相关的心肌结构建模，这导致功能障碍。因此，这种重构已成为心力衰竭治疗的新靶点，以改善疾病的发病率和死亡率。肝细胞生长因子最初作为成熟肝细胞的有效有丝分裂原克隆，在各种疾病模型中具有血管生成、抗凋亡和抗纤维化活性，尽管在心脏中未得到证实。本研究从以下几个方面阐明了HGF在心脏中的作用：1）我们新发现HGF是一种内源性心脏保护因子，即HGF和c-Met/HG 关于我们 F受体在缺血再灌注损伤后迅速上调，HGF给药显著抑制缺血再灌注损伤的病理进展。2)终末期DCM仓鼠心肌TGF-β1水平升高，而心肌HGF水平显著降低。当仓鼠每天接受重组人HGF给药3周时，心肌纤维化面积显著减少，而心肌细胞横截面积显著增加。TGF-β1和I、III型胶原mRNA水平下调，心功能不全的进展受到明显抑制。3)将HGF基因转染快速起搏诱导的DCM犬心肌，可促进DCM犬左室功能、室壁厚度、细胞直径和血管生成的恢复，减少心肌纤维化和心肌细胞凋亡。我们的研究结果表明，肝细胞生长因子或肝细胞生长因子基因治疗可能是一种新的治疗心力衰竭的策略。少

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