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

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.

• Authors: 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
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 107 Issue 1 Pg. 239 (Jan 2012) ISSN: 1435-1803 [Electronic] Germany
• PMID: 22202974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Cell Proliferation
• Endothelial Cells (physiology)
• Fibrosis
• Genetic Therapy
• Heart Failure (metabolism)
• Humans
• MAP Kinase Signaling System
• Mice
• Mice, Knockout
• Mice, Transgenic
• Myocardial Infarction (immunology, metabolism, mortality)
• Myocardium (pathology)
• Neovascularization, Physiologic
• Proto-Oncogene Proteins c-akt (metabolism)
• Ventricular Remodeling