Autophagy maintains cellular homeostasis by lysosomal degradation and recycling of damaged/dysfunctional organelles (such as mitochondna), removal of aggregated proteins, and the provision of energy to cells in times of stress. It has been recognized that an inverse relationship between autophagy and inflammation exists, such that as autophagy declines, inflammation increases. Aging affects autophagy and inflammation such that autophagy declines and a chronic inflammatory state develops. It has been argued that chronic inflammation enhances the susceptibility to age-related diseases/disabilities. Metabolic syndrome (MetS) is a cluster of risk factors that identifies a population with increased risk of developing type II diabetes and cardiovascular disease. This condition is brought on by high-fat diets, is prevalent in the aged and is coupled with elevated basal levels of inflammatory cytokines. IL-1B and IL-18 are early, pro-inflammatory cytokines that are known to induce further inflammation and are associated with metabolic syndrome. Recent work demonstrates a link between autophagy and the NLRP3 inflammasome and N F - K B pathways that induce IL-1B and IL-18 production [For the purpose of this proposal, this is called autophagy/mitophagy-to-IL-1B/18 pathway.]. The overall goal of this application is to test the hypothesis that autophagy and inflammation in the cardiac ischemia/reperfusion (l/R) model are interdependent and modulation of autophagy will affect levels of inflammation and hence the severity of cardiac injury post l/R. To test the hypothesis. we will use mice that have their autophagic activity experimentally manipulated (Aim 1), aged mice that naturally have diminished autophagy (Aim 2), and rodents/swine with MetS that exhibit elevated levels of inflammation (Aim 3). Specifically: ? Aim 1 will assess the effect of modulating autophagy on inflammation and cardiac injury after permanent coronary artery occlusion and the role of the mitophagy-to-IL-1B/18 pathway in infarct size and remodeling;
Aim 2 will assess the effect of age on autophagy and inflammation in cardiac l/R;
Aim 3 will assess the effect of MetS on autophagy and inflammation in cardiac l/R. These studies will identify step(s) in the autophagy/mitophagy-to-IL-1B/18 pathway that can be modulated to reduce inflammation, preserve autophagy and thus, ameliorate injury post l/R.
The studies in this application are focused on understanding the mechanism by which autophagy and inflammation are linked in the cardiac ischemia/reperfusion model using aged animals and animals with metabolic syndrome. In so doing, we may elucidate methods that will reduce inflammation and hence reduce cardiac damage and improve outcome.
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