Nakano Jota, Marui Akira, Muranaka Hiroyuki, Masumoto Hidetoshi, Noma Hisashi, Tabata Yasuhiko, Ido Akio, Tsubouchi Hirohito, Ikeda Tadashi, Sakata Ryuzo
Department of Cardiovascular Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
Interact Cardiovasc Thorac Surg. 2014 Mar;18(3):300-7. doi: 10.1093/icvts/ivt512. Epub 2013 Dec 9.
Myocarditis is considered one of the major causes of dilated cardiomyopathy. Hepatocyte growth factor (HGF) has pleiotropic activities that promote tissue regeneration and facilitate functional improvement of injured tissue. We investigated whether the epicardial sustained-release of HGF, using gelatin hydrogel sheets, improves cardiac function in a chronic myocarditis rat model.
Six weeks after Lewis rats were immunized with porcine cardiac myosin to establish autoimmune myocarditis, HGF- or normal saline (NS)-incorporated gelatin hydrogel sheets were applied to the epicardium (G-HGF and G-NS, respectively). At either 2 or 4 weeks after treatment, these were compared with the Control myocarditis group. Cardiac function was evaluated by echocardiography and cardiac catheterization. Development of fibrosis was determined by histological study and expression of transforming growth factor-β1 (TGF-β1). Bax and Bcl-2 levels were measured to evaluate apoptotic activity.
At both points, fractional shortening and end-systolic elastance were higher in the G-HGF group than in the Control and G-NS groups (P < 0.01). Fractional shortening at 2 weeks of each group were as follows: 31.0 ± 0.9%, 24.8 ± 2.7% and 48.6 ± 2.6% (Control, G-NS and G-HGF, respectively). The ratio of the fibrotic area of the myocardium was lower in the G-HGF group than in the Control and G-NS groups at 2 weeks (G-HGF, 8.8 ± 0.9%; Control, 17.5 ± 0.2%; G-NS, 15.6 ± 0.7%; P < 0.01). The ratio at 4 weeks was lower in the G-HGF group than in the G-NS group (10.9 ± 1.4% vs 18.5 ± 1.3%; P < 0.01). The mRNA expression of TGF-β1 in the G-HGF group was lower than in the Control group at 2 weeks (0.6 ± 0.1 vs 1.1 ± 0.2) and lower than that in the G-NS group at 4 weeks (0.7 ± 0.1 vs 1.3 ± 0.2). The Bax-to-Bcl-2 ratios at both points were lower in the G-HGF group than in the Control group.
Sustained-released HGF markedly improves cardiac function in chronic myocarditis rats. The antifibrotic and antiapoptotic actions of HGF may contribute to the improvement. HGF-incorporated gelatin hydrogel sheet can be a new therapeutic modality for myocarditis.
心肌炎被认为是扩张型心肌病的主要病因之一。肝细胞生长因子（HGF）具有多种活性，可促进组织再生并有助于受损组织的功能改善。我们研究了使用明胶水凝胶片将HGF进行心外膜缓释是否能改善慢性心肌炎大鼠模型的心脏功能。
用猪心肌肌凝蛋白免疫Lewis大鼠以建立自身免疫性心肌炎，6周后，将含HGF或生理盐水（NS）的明胶水凝胶片应用于心外膜（分别为G-HGF和G-NS）。在治疗后2周或4周，将这些与对照组心肌炎组进行比较。通过超声心动图和心导管检查评估心脏功能。通过组织学研究和转化生长因子-β1（TGF-β1）的表达来确定纤维化的发展。测量Bax和Bcl-2水平以评估细胞凋亡活性。
在两个时间点，G-HGF组的缩短分数和收缩末期弹性均高于对照组和G-NS组（P<0.01）。每组2周时的缩短分数如下：31.0±0.9%、24.8±2.7%和48.6±2.6%（分别为对照组、G-NS组和G-HGF组）。2周时，G-HGF组心肌纤维化面积的比例低于对照组和G-NS组（G-HGF，8.8±0.9%；对照组，17.5±0.2%；G-NS，15.6±0.7%；P<0.01）。4周时，G-HGF组的比例低于G-NS组（10.9±1.4%对18.5±1.3%；P<0.01）。2周时，G-HGF组中TGF-β1的mRNA表达低于对照组（0.6±0.1对1.1±0.2），4周时低于G-NS组（0.7±0.1对1.3±0.2）。两个时间点G-HGF组的Bax与Bcl-2比值均低于对照组。
缓释HGF可显著改善慢性心肌炎大鼠的心脏功能。HGF的抗纤维化和抗凋亡作用可能有助于这种改善。含HGF的明胶水凝胶片可为心肌炎提供一种新的治疗方式。
