Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction
Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction
复制标题
细胞 FLICE 抑制蛋白可预防心肌梗死后的心脏重塑
DOI：
10.1007/s00395-011-0239-z
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发表时间：
2012-01-01
影响因子：
9.5
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
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作者：
Xiao, Jinfeng;Moon, Mark;Li, Hongliang
细胞FLICE抑制蛋白（cFLIP）是肿瘤坏死因子信号传导途径的成员和细胞凋亡的调节因子，它在心肌梗死（MI）后的心脏重塑中发挥作用，但在很大程度上尚未表征。本研究旨在确定cFLIP作为梗死后心脏重构的潜在介质的功能。我们的研究结果表明，cFLIP表达减少失败的人类和小鼠梗死后心脏。通过永久性结扎左前降支动脉，对基因工程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）和非转基因对照进行MI。通过超声心动图和压力-容积环分析评估心脏结构和功能。评估心肌细胞凋亡、炎症、血管生成和纤维化。MI后28天，与WT小鼠相比，HET小鼠表现出左心室（LV）收缩功能障碍、扩张和重塑加重。HET小鼠的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相关。TG小鼠在MI后表现出相反的表型。此外，在HET和WT小鼠中，腺病毒介导的cFLIP过表达降低了LV扩张，改善了LV功能和重塑。信号事件的进一步分析表明，cFLIP通过中断JNK 1/2信号传导和增强Akt信号传导促进心脏保护。总之，我们的研究结果表明，cFLIP防止梗死后心脏重构的发展。因此，cFLIP基因递送显示出作为治疗MI后心力衰竭的临床上强大的和新的治疗策略的前景。
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.