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

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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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Acknowledgments

We thank Dr. Wen-Chen Yeh for providing cFLIP heterozygous mice (cFLIP+/−, HET, CD1 background) and replication-defective adenoviral vectors encoding for the entire coding region of the mouse cFLIP gene. We thank Dr. Annunciata Vecchi for providing H5V mouse heart microvascular endothelial cell line. This study was supported by the National Natural Science Foundation of China (grants 30900524 30972954, 81000036, 81170086, 81000089, and 81000095), and the Support Program for Disciplinary Leaders in Wuhan (200951830561), the National Science and Technology Support Program (2012BAI39B05 and 2011BAI15B02), the Hubei Funds for Distinguished Young Scientists (2010CDA092) and the National Basic Research Program of China (2011CB503902).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People’s Republic of China

    Jinfeng Xiao, Ling Yan, Yan Zhang, Jing Lu, Hongjing Guan, Dingsheng Jiang, Hong Jiang & Hongliang Li

  2. Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People’s Republic of China

    Jinfeng Xiao, Ling Yan, Yan Zhang, Jing Lu, Hongjing Guan, Dingsheng Jiang, Hong Jiang & Hongliang Li

  3. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Toronto, ON, M5S 3E2, Canada

    Mark Moon, Min Nian & Peter P. Liu

  4. Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    Chen Liu & Manyin Chen

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  1. Jinfeng Xiao
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  2. Mark Moon
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  10. Dingsheng Jiang
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  11. Hong Jiang
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  13. Hongliang Li
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Correspondence to Hongliang Li.

Additional information

J. Xiao, M. Moon and L. Yan contribute equally to this work.

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Xiao, J., Moon, M., Yan, L. et al. Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. Basic Res Cardiol 107, 239 (2012). https://doi.org/10.1007/s00395-011-0239-z

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