Thirty years of cardioprotection research have failed to yield a therapeutic intervention effective in the clinical setting, despite numerous agents shown to be effective in animal studies. This failure is widely attributed to the use of young healthy animals for these studies, rather than animals with the comorbid conditions encountered in humans suffering from myocardial ischemia and reperfusion arising from acute myocardial infarction or cardiac surgery. Advanced age, metabolic syndrome, and diabetes have been shown to interfere with cardioprotection. Moreover, inflammation is increased in the elderly and in aged animals, as well as in the setting of metabolic syndrome. Importantly, autophagy is diminished with age or metabolic syndrome. The central theme of this proposal states that impaired autophagy is a feature of metabolic syndrome and aging; impaired autophagy contributes to inflammation, limits cardioprotection, and exacerbates postinfarction remodeling. Impaired autophagy prevents mitophagy essential for preconditioning, and limits mitochondrial turnover, resulting in the accumulation of inefficien, ROS-producing mitochondria that activate inflammatory signaling pathways. The studies proposed in the three Projects (Cardioprotection, Inflammation, and Mitochondrial Turnover) will test these interconnected hypotheses, identify agents that can upregulate autophagy despite advanced age or the presence of metabolic syndrome, and thereby restore cardioprotection and improve postinfarction outcomes. In addition to these practical translational objectives, the individual projects contain specific aims which will provide detailed molecular insights into process of cardioprotection, as well as the alterations arising as a result of aging or metabolic syndrome (MetS). The technology-driven Proteomics Core and the Animal Physiology, Surgery, and Imaging Core will support all projects and will also advance existing technology. At the end of five years, our common goals are to: Establish the impact of age, diet-induced obesity, and MetS on autophagy and the ability to achieve cardioprotection through ischemic preconditioning, postconditioning, or pharmacologic conditioning Determine whether an autophagy-inducing drug can mitigate the effects of age or metabolic syndrome to ameliorate adverse postinfarction remodeling or to enable successful cardioprotection. Establish the contribution of autophagy/mitophagy to inflammation in the context of acute myocardial ischemia and postinfarction remodeling. Identify protein signatures of impaired autophagy or impaired mitochondrial turnover, which would predict unresponsiveness to cardioprotective interventions. Identify protein biomarkers for the cardioprotected state, indicated by elimination of damaged mitochondria or up-regulated autophagy, validate in swine models, and study human heart tissue.
These studies will help us understand why cardiovascular outcomes are worse in the elderly or those with conditions such as diabetes and obesity. We will define biochemical signatures of cardioprotection and will determine if up-regulating autophagy (intracellular recycling) can decrease inflammation and improve cardiovascular outcome in relevant animal models.
| Chung, Heaseung Sophia; Murray, Christopher I; Van Eyk, Jennifer E (2018) A Proteomics Workflow for Dual Labeling Biotin Switch Assay to Detect and Quantify Protein S-Nitroylation. Methods Mol Biol 1747:89-101 |
| Crupi, Annunziata N; Nunnelee, Jordan S; Taylor, David J et al. (2018) Oxidative muscles have better mitochondrial homeostasis than glycolytic muscles throughout life and maintain mitochondrial function during aging. Aging (Albany NY) 10:3327-3352 |
| Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838 |
| Coronado, Michael; Fajardo, Giovanni; Nguyen, Kim et al. (2018) Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand. Circ Res 122:282-295 |
| Stastna, Miroslava; Thomas, Amandine; Germano, Juliana et al. (2018) Dynamic Proteomic and miRNA Analysis of Polysomes from Isolated Mouse Heart After Langendorff Perfusion. J Vis Exp : |
| Kloner, Robert A; Brown, David A; Csete, Marie et al. (2017) New and revisited approaches to preserving the reperfused myocardium. Nat Rev Cardiol 14:679-693 |
| Giricz, Zoltán; Varga, Zoltán V; Koncsos, Gábor et al. (2017) Autophagosome formation is required for cardioprotection by chloramphenicol. Life Sci 186:11-16 |
| Delbridge, Lea M D; Mellor, Kimberley M; Taylor, David J et al. (2017) Myocardial stress and autophagy: mechanisms and potential therapies. Nat Rev Cardiol 14:412-425 |
| Chung, Heaseung Sophia; Kim, Grace E; Holewinski, Ronald J et al. (2017) Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 114:E10763-E10771 |
| Gottlieb, Roberta A; Thomas, Amandine (2017) Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart. Curr Pathobiol Rep 5:161-169 |
Showing the most recent 10 out of 41 publications
