Clinical and basic science studies demonstrate that nuclear factor-kappaB (NF-kappaB) is activated after ischemia/reperfusion (I/R) and is positively correlated with increased morbidity and mortality in patients with unstable angina. Although we have shown that the overall effect of NF-kappaB in the heart after I/R is injurious, NF-kappaB is capable of activating cell-survival/growth factors and genes associated with cardioprotective and anti-apoptotic effects as well as genes associated with inflammation and apoptotic cell death. Yet there is little understanding of how antithetical pathophysiological processes are regulated by different and possibly overlapping sets of NF-kappaB-dependent genes. The goal of this proposal is to delineate the mechanisms by which NF-kappaB contributes to ischemia/reperfusion injury on one hand and the cardioprotective effects of late ischemic PC on the other. The central hypothesis is that NF-kappaB is a key integrator of multiple signaling pathways, including cytokines and mitogen-activated protein kinases (MAPK), and acts, via regulation of NF-kappaB-dependent genes, to influence cell death/survival after I/R and during development of late PC. This hypothesis is based upon Preliminary Results that genetic blockade of NF-kappaB affects I/R injury and abrogates the protective effects of late PC against MI in association with modulation of critical genes including iNOS, Cox2, HSP70 and metallothionein.
The specific Aims of the proposal are:
Aim 1. Determine the role of NF-kappaB-dependent gene expression in I/R injury and late ischemic PC.
Aim 2. Delineate the signaling pathways that activate NF-kappaB and the key cross-talk interactions that occur post-I/R and after late ischemic PC.
Aim 3. Determine the transcriptional mechanism by which NF-kappaB affects gene expression to evoke cell death after I/R and cardioprotection consequent to late ischemic PC. This proposal is innovative in that it addresses a novel concept; that NF-kappaB acts as a signaling integrator or """"""""hub"""""""" that affects cardiac pathophysiology by the integrative regulation of NF-kappaB-dependent genes. The expected contribution of the research is attainment of new knowledge regarding the mechanism by which NF-kappaB-dependent gene expression mediates I/R injury and evokes the cardioprotective effects of late PC. This is significant because a mechanistic understanding is necessary to develop strategies to block NF-kappaB and specific sets of NF-kappaB-dependent genes for the development of novel therapeutic regimens that maximize the beneficial effects while limiting the deleterious effects of NF-kappaB signaling.
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