Abstract 961: cFLIP, a Crucial Mediator of Cardiac Remodeling
The role of a master apoptosis regulator, cFLIP (FLICE-inhibitory protein), a member of the TNF signaling pathway, in the process of cardiac remodeling following myocardial infarction (MI) leading to heart failure is unknown. In our study, we sought to directly elucidate the contributions of cFLIP as a potential mediator of remodeling post myocardial infarction.
Results: In the MI models, cFLIP+/− mice exhibited significantly reduced systolic pressure, developed pressure, and dP/dt compared to the wild-type control mice. The reduced cardiac function in cFLIP+/− mice was partially a result of significantly larger MI scar (70% vs 35%). The left ventricle measured by left ventricular circumferences in the cFLIP+/− mice was also markedly dilated compared to the wild-type control mice post MI (12.2 mm vs 8.5 mm). Both TUNEL and Western Blot analysis demonstrated that there were significantly increases in the level of apoptosis at all regions of the heart in cFLIP+/− mice post MI. At the boarder region of MI, cell proliferation and angiogenesis were markedly decreased in the cFLIP+/− mice compared to the control mice. Decreased cFLIP level in mice led to an increased reparative fibrosis. This was confirmed to be mediated through the activation of IFN-β, TSP2, and cTGF signaling pathways. Over-expression of cFLIP via adeno-virus assisted gene therapy significantly improved systolic pressure, stroke volume, and cardiac output in both cFLIP+/− mice and wild-type control mice post MI as a result of decreased apoptosis and fibrosis in mice.
Conclusion: We demonstrated that a decreased level of cFLIP in myocardium resulted in significantly damaged cardiac function post MI. The unfavoured remodeling was the result of increased myocyte loss, excessive fibrosis and decreased cell proliferation and angiogenesis in the heart. We identified a novel mechanism whereby cFLIP regulates collagen production during cardiac remodeling. Furthermore, we showed the functional rescue and improvement of cardiac remodeling in mice by cFLIP gene therapy. Therefore, cFLIP is a critical mediator of cardiac remodeling post MI. Our study offers an important therapeutic opportunity in regulating cFLIP post infarction to achieve better remodeling and functional recovery.