Cardiovascular disease, and myocardial infarction (MI) in particular, remains a major burden in the developed world today. In fact, the remodeling process, which follows the initial ischemic episode of MI, is a major determinant of heart failure. Although several key mechanistic pathways involving cell growth and death have been identified, there is limited knowledge surrounding the role of the innate immune response as a positive or negative regulator of cardiac remodeling. Recent data strongly support a role for key regulatory components within the toll-like receptor (TLR) family as potent modulators of cardiac remodeling post-MI. It has been demonstrated that targeted gene knockdown of TLR4, as well as downstream adaptor proteins and kinases, significantly improve cardiac function and overall survival. While the well-known NF-κB transcriptional factor that is downstream to TLR4 signaling has been linked to remodeling, there has been no evidence thus far describing a role of the parallel interferon regulatory factor-3 (IRF3) signaling cascade in any facet of this process. Several key findings suggest that IRFs contribute to both cell growth and apoptosis, thus providing an appealing, and novel target for interrogation. In this thesis I describe how IRF3 contributes to maladaptive remodeling post-MI. In my first set of experiments, I demonstrate that IRF3 is acutely upregulated within the cardiomyocyte following MI and that this response contributes to excessive apoptosis post-MI. A targeted deletion of the IRF3 gene enhances cardiac function, decreases infarct size, and improves survival following MI. In the second set of experiments I demonstrate that IRF3 attenuates angiogenesis at the ischemic border zone by upregulating the expression of thrombospondins. I have shown that IRF3 deficiency, which liberates endogenous anti-angiogenic signals, promotes angiogenesis following ischemic injury. These data suggest that IRF3 is a potent regulator of cardiac remodeling and may be an effective therapeutic target to ameliorate maladaptive cardiac repair post-MI.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/35159 |
| Date | 19 March 2013 |
| Creators | de Couto, Geoffrey |
| Contributors | Liu, Peter |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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