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

心衰是由扩张型心肌病（DCM）和心肌梗死等各种心脏疾病引起的，是发达国家的主要死亡原因，但除心脏移植外，尚无有效的治疗方法。心衰的病理生理特征是心肌的结构建模，与心肌细胞肥大、细胞死亡和细胞外基质过度沉积有关，从而导致功能障碍。因此，这种重塑已成为心力衰竭新的治疗靶点，以提高疾病的发病率和死亡率。肝细胞生长因子最初被克隆为成熟肝细胞的有效丝裂原，在各种疾病模型中具有血管生成、抗凋亡和抗纤维化活性，尽管尚未在心脏中得到证实。在本研究中，我们从以下几个方面阐述了HGF在心脏中的作用；1)我们新发现HGF是内源性心脏保护因子，与HGF和c-Met/HG一样，更多的F受体在缺血再灌注损伤后迅速上调，给药HGF可显著抑制缺血再灌注损伤的病理进展。2) DCM仓鼠终末期心肌TGF-β1水平升高，心肌HGF水平显著降低，而心肌TGF-β1被认为是慢性纤维化疾病的关键纤维化因子。每天给药重组人造血干细胞3周后，心肌纤维化面积明显减少，心肌细胞横截面积明显增加。TGF-β1及I型、III型胶原mRNA水平下调，心功能障碍进展明显受到抑制。3) HGF基因转染到犬快速起搏诱导的DCM心肌中，可促进左室功能、左室壁厚度、细胞直径和血管生成的恢复，减少纤维化和心肌细胞凋亡。我们的研究结果表明HGF或HGF基因治疗可能是心力衰竭的一种新的治疗策略。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