Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hypertension. 2012 May;59(5):958-65. doi: 10.1161/HYPERTENSIONAHA.111.183905. Epub 2012 Mar 5.
The purpose of this study was to investigate the effect of hepatocyte growth factor (HGF) on the pathogenesis of cardiac fibrosis induced by pressure overload in mice. Although cardiac fibrosis is attributed to excess pathological deposition of extracellular matrix components, the mechanism remains unclear. Recent reports revealed that α-smooth muscle actin-expressing myofibroblasts are primarily responsible for fibrosis. It is believed that myofibroblasts are differentiated from resident fibroblasts, whereas the transformation of vascular endothelial cells into myofibroblasts, known as endothelial-mesenchymal transition, has been suggested to be intimately associated with perivascular fibrosis. Thus, we hypothesized that HGF prevents cardiac fibrosis by blocking these pathways. We analyzed the pressure-overloaded HGF-transgenic mouse model made by transverse aortic constriction. Human coronary artery endothelial cells and human cardiac fibroblasts were examined in vitro after being treated with transforming growth factor-β1 or angiotensin II with or without HGF. The amount of cardiac fibrosis significantly decreased in pressure-overloaded HGF-transgenic mice compared with pressure-overloaded nontransgenic controls, particularly in the perivascular region. This was accompanied by a reduction in the expression levels of fibrosis-related genes and by significant preservation of echocardiographic measurements of cardiac function in the HGF-transgenic mice (P<0.05). The survival rate 2 months after transverse aortic constriction was higher by 45% (P<0.05). HGF inhibited the differentiation of human coronary artery endothelial cells into myofibroblasts induced by transforming growth factor-β1 and the phenotypic conversion of human cardiac fibroblasts into myofibroblasts. We conclude that HGF reduced cardiac fibrosis by inhibiting endothelial-mesenchymal transition and the transformation of fibroblasts into myofibroblasts.
本研究旨在探讨肝细胞生长因子（HGF）对压力超负荷诱导的小鼠心肌纤维化发病机制的影响。尽管心肌纤维化归因于细胞外基质成分的病理性过度沉积，但具体机制尚不清楚。最近的报道表明，α-平滑肌肌动蛋白表达的肌成纤维细胞是纤维化的主要原因。据信，肌成纤维细胞是由驻留成纤维细胞分化而来的，而血管内皮细胞向肌成纤维细胞的转化，即内皮-间质转化，与血管周围纤维化密切相关。因此，我们假设 HGF 通过阻断这些途径来预防心肌纤维化。我们分析了通过横主动脉缩窄制作的压力超负荷 HGF 转基因小鼠模型。体外用人转化生长因子-β1或血管紧张素 II 处理人冠状动脉内皮细胞和人心房成纤维细胞，并加入或不加入 HGF。与压力超负荷非转基因对照组相比，压力超负荷 HGF 转基因小鼠的心肌纤维化量显著减少，特别是在血管周围区域。这伴随着纤维化相关基因表达水平的降低，以及 HGF 转基因小鼠心脏功能的超声心动图测量显著保留（P<0.05）。横主动脉缩窄后 2 个月的存活率提高了 45%（P<0.05）。HGF 抑制了转化生长因子-β1诱导的人冠状动脉内皮细胞向肌成纤维细胞的分化和人心房成纤维细胞向肌成纤维细胞的表型转化。我们得出结论，HGF 通过抑制内皮-间质转化和纤维母细胞向肌成纤维细胞的转化来减少心肌纤维化。
