犬缺血心肌注射肝细胞生长因子致血管新生的效应

Effect of injection with hepatocyte growth factor on angiogenesis in myocardium of dogs with myocardial ischemia

目的探讨心肌梗死犬心肌内注射不同剂量肝细胞生长因子(hepatocyte growth factor,HGF)基因致血管新生的分子机制。方法 16只体质量11～13kg、1.5岁雄性杂种犬用于实验,采用冠状动脉结扎法建立犬心肌梗死(myocardial infarction,MI)动物模型,分为4组:500μg及1000μgHGF裸质粒治疗组、假手术组(Sham组)、MI无干预组(n=4)。28d后检测犬缺血心肌中HGF、血管内皮细胞生长因子(VEGF)、CD31、血小板Ⅷ因子的表达,计算微血管计数,分析血管新生与HGF、VEGF表达的相关性。结果 HGF基因治疗能上调心肌中CD31、VEGF的表达(P<0.01),1000μgHGF治疗组VEGF、CD31mRNA相对表达为0.82、0.39,500μgHGF治疗组VEGF、CD31mRNA相对表达为0.47、0.21,MI组VEGFmRNA相对表达为0.09,MI组无CD31表达。HGF增加梗死心肌的血管新生,1000μg、500μgHGF治疗组以及MI组MVD分别为(126.4±10.6)、(79.8±6.0)、(21.7±2.5),差异显著(P<0.01)。血管新生与VEGF及HGF表达呈正相关(P<0.01),血管新生与VEGF表达均随HGF表达量递增(P<0.05)。结论 HGF可能通过自身的促血管新生作用,或促进内源性VEGF分泌,共同增加犬MI后缺血心肌血管新生。

Objective To study the molecular mechanism of injection with hepatocyte growth factor （HGF） at different doses on angiogenesis in myocardium of dogs with acute myocardial infarction （MI）.Methods Sixteen 1.5-year-old male hybrid dogs,weighing 11-13 kg,were divided into 500 μg HGF treatment group,1 000 μg HGF treatment group,sham operation group,and no MI interference group,4 dogs in each group.Expressions of VEGF,HGF,CD31,and platelet factor Ⅷ in myocardium of dogs with MI were detected,the number of micro blood vessels was calculated,and correlation between angiogenesis and expression of HGF and VEGF was analyzed in 28 d after the model was established.Results HGF gene therapy could up-regulate the expression of CD31 and VEGF.The expression of CD31 and VEGF mRNA was 0.82 and 0.39 respectively in 1 000 μg HGF group,and 0.47 and 0.21 respectively in 500 μg HGF group.The expression of VEGF mRNA was 0.09 and no expression of CD31 mRNA was found in MI group.HGF could increase the angiogenesis in infracted myocardium.The microvascular density was 126.4±10.6,79.8±6.0,and 21.7±2.5/mm2,respectively,in 1 000 μg HGF group,500 μg HGF group,and MI group （P0.01）.The angiogenesis was positively correlated with the expression of VEGF and HGF （P0.01）.The angiogenesis and expression of VEGF increased with the increasing HGF dose.Conclusion HGF increases angiogenesis in dogs after myocardial ischemia by promoting formation of blood vessels and secretion of endogenous VEGF.