Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
Basic Res Cardiol. 2012 Jan;107(1):239. doi: 10.1007/s00395-011-0239-z. Epub 2011 Dec 28.
Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.
细胞型 Fas 相关死亡域蛋白（cFLIP）是肿瘤坏死因子信号通路的成员，也是细胞凋亡的调节因子，它在心梗后心脏重构中发挥作用，但目前仍知之甚少。本研究旨在确定 cFLIP 作为潜在的梗塞后心脏重构中介物的作用。我们的研究结果表明，在衰竭的人和鼠梗塞后心脏中 cFLIP 的表达减少。通过永久性结扎左前降支，将基因工程设计的 cFLIP 杂合（cFLIP+/-, HET）小鼠、心脏特异性 cFLIP 过表达转基因（TG）小鼠及其各自的野生型（WT）和非转基因对照小鼠诱导心梗。通过超声心动图和压力-容积环分析评估心脏结构和功能。在心肌中评估凋亡、炎症、血管生成和纤维化。与 WT 小鼠相比，HET 小鼠在心梗 28 天后表现出更严重的左心室（LV）收缩功能障碍、扩张和重构。HET 小鼠 LV 功能受损与梗死面积增加、肥大、凋亡、炎症和间质纤维化以及毛细血管密度降低有关。TG 小鼠心梗后表现出相反的表型。此外，腺病毒介导的 cFLIP 过表达可减少 LV 扩张，并改善 HET 和 WT 小鼠的 LV 功能和重构。对信号事件的进一步分析表明，cFLIP 通过中断 JNK1/2 信号和增强 Akt 信号来促进心脏保护。总之，我们的研究结果表明 cFLIP 可防止梗塞后心脏重构的发生。因此，cFLIP 基因传递有望成为治疗心梗后心力衰竭的一种强大而新颖的临床治疗策略。
