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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL112730-01A1
Application #
8476844
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schwartz, Lisa
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$2,156,842
Indirect Cost
$612,056
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Pepe, Salvatore; Mentzer Jr, Robert M; Gottlieb, Roberta A (2014) Cell-permeable protein therapy for complex I dysfunction. J Bioenerg Biomembr 46:337-45
Andres, Allen M; Hernandez, Genaro; Lee, Pamela et al. (2014) Mitophagy is required for acute cardioprotection by simvastatin. Antioxid Redox Signal 21:1960-73
Linton, Phyllis-Jean; Thoman, Marilyn L (2014) Immunosenescence in monocytes, macrophages, and dendritic cells: lessons learned from the lung and heart. Immunol Lett 162:290-7
Hernandez, Genaro; Thornton, Christine; Stotland, Aleksandr et al. (2013) MitoTimer: a novel tool for monitoring mitochondrial turnover. Autophagy 9:1852-61
Ferree, Andrew W; Trudeau, Kyle; Zik, Eden et al. (2013) MitoTimer probe reveals the impact of autophagy, fusion, and motility on subcellular distribution of young and old mitochondrial protein and on relative mitochondrial protein age. Autophagy 9:1887-96
Riehle, Christian; Wende, Adam R; Sena, Sandra et al. (2013) Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. J Clin Invest 123:5319-33