Postinfarction gene therapy against transforming growth factor-β signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure
Postinfarction gene therapy against transforming growth factor-β signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure
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DOI：
10.1161/01.cir.0000165066.71481.8e
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发表时间：
2005-05-17
期刊：
影响因子：
37.8
通讯作者：
Fujiwara, H
中科院分区：
文献类型：
--
作者：
Okada, H;Takemura, G;Fujiwara, H
背景--心肌梗死后心脏纤维化和进行性衰竭是主要的病理生理特征.我们研究了抑制转化生长因子-β（TGF-β）信号传导对MI后心脏纤维化和心室重塑和function.Methods和Results的影响- MI诱导小鼠左冠状动脉结扎。携带可溶性TGF-β II型受体的腺病毒（Ad.然后在MI后第3天将TGF-β的竞争性抑制剂CAG-sT β RII（对照，Ad. CAG-LacZ）。在sT β RII治疗的小鼠中，MI后存活率显著提高（96%，对照组为71%），这也显示了MI后4周心室扩张的显著减弱和功能改善。同时，组织学分析显示纤维组织形成减少。尽管两组的MI大小没有差异，但sT β RII治疗组的MI厚度更大，周长更小;在梗死区域内，α-平滑肌肌动蛋白阳性细胞丰富，这可能有助于梗死收缩。在sT β RII治疗组中，亚急性期（MI后10天）肉芽组织中肌成纤维细胞的凋亡频率较低，sT β RII直接抑制Fas诱导的培养肌成纤维细胞凋亡。最后，如果在慢性阶段（MI后4周）开始，用sT β RII治疗MI荷瘤小鼠是无效的。结论-梗死后基因治疗旨在抑制TGF-β信号传导，通过影响心脏纤维化和梗死组织动力学（细胞凋亡抑制和梗死收缩）减轻心脏重塑。这表明，这种疗法可能代表了一种新的方法来治疗心肌梗死后心力衰竭，适用于在亚急性阶段。
Background - Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-beta (TGF-beta) signaling on post-MI cardiac fibrosis and ventricular remodeling and function.Methods and Results - MI was induced in mice by left coronary artery ligation. An adenovirus harboring soluble TGF-beta type II receptor ( Ad. CAG-sT beta RII), a competitive inhibitor of TGF-beta, was then injected into the hindlimb muscles on day 3 after MI ( control, Ad. CAG-LacZ). Post-MI survival was significantly improved among sT beta RII-treated mice (96% versus control at 71%), which also showed a significant attenuation of ventricular dilatation and improved function 4 weeks after MI. At the same time, histological analysis showed reduced fibrous tissue formation. Although MI size did not differ in the 2 groups, MI thickness was greater and circumference was smaller in the sT beta RII-treated group; within the infarcted area, alpha-smooth muscle actin - positive cells were abundant, which might have contributed to infarct contraction. Apoptosis among myofibroblasts in granulation tissue during the subacute stage ( 10 days after MI) was less frequent in the sT beta RII-treated group, and sT beta RII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sT beta RII was ineffective if started during the chronic stage ( 4 weeks after MI).Conclusions - Postinfarction gene therapy aimed at suppressing TGF-beta signaling mitigates cardiac remodeling by affecting cardiac fibrosis and infarct tissue dynamics ( apoptosis inhibition and infarct contraction). This suggests that such therapy may represent a new approach to the treatment of post-MI heart failure, applicable during the subacute stage.