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01.01.2012 | Original Contribution | Ausgabe 1/2012

Basic Research in Cardiology 1/2012

Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction

Zeitschrift:
Basic Research in Cardiology > Ausgabe 1/2012
Autoren:
Jinfeng Xiao, Mark Moon, Ling Yan, Min Nian, Yan Zhang, Chen Liu, Jing Lu, Hongjing Guan, Manyin Chen, Dingsheng Jiang, Hong Jiang, Peter P. Liu, Hongliang Li
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00395-011-0239-z) contains supplementary material, which is available to authorized users.
J. Xiao, M. Moon and L. Yan contribute equally to this work.

Abstract

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.

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Zusatzmaterial
Supplementary material 1 (DOC 42 kb)
395_2011_239_MOESM1_ESM.doc
Supplementary material 2 (PPT 3720 kb)
395_2011_239_MOESM2_ESM.ppt
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