It is well established that diabetes leads to an increased risk for the development of heart failure independent of other risk factors such as hypertension and ischemic heart disease; however, there is no consensus as to the mechanisms involved or the most appropriate treatment strategies. High levels of glucose activate the hexosamine biosynthesis pathway (HBP) and increase the levels of N-acetylglucosamine (O-GlcNAc) on cytoplasmic and nuclear proteins. Our preliminary data suggest that the HBP and protein O-GlcNAcylation contribute to diabetes-induced myocyte dysfunction. Indeed, increased flux through HBP may represent a critical link between metabolic dysfunction and impaired cardiac function following the development of diabetes. Therefore, the overall hypothesis of this proposal is that the dysregulation of myocardial carbohydrate and fatty acid metabolism in Type-2 diabetes leads to increased flux through the HBP and results in increased O-GlcNAcylation and altered behavior of proteins involved in regulating normal cardiomyocyte function. Consequently in hearts from normal, insulin resistant and diabetic rats we will: 1) determine the impact of altered carbohydrate and fatty acid metabolism on flux through the HBP, phosphorylation of the MAPK and the PI3K/Akt/GSK pathways; 2) determine whether increased HBP flux and protein O-GlcNAcylation in Type-2 diabetes contributes to impaired cardiac function including altered response to a-adrenergic stimulation and activation of pro-apoptotic and inhibition of prosurvival components of the MAPK and PI3K/Akt/GSK pathways; 3) Identify specific proteins that are modified including those involved in a-adrenergic signaling and the MAPK and the PI3K/Akt/GSK pathways that are integral to the adverse effects of diabetes on the heart. These studies bring together 13C-NMR spectroscopy with cellular, molecular and proteomic techniques to evaluate the interactions between glucose and fatty acid utilization, the HBP, protein O-GlcNAcylation and cardiac function in hearts from normal and diabetic animals. We will use the Zucker diabetic fatty rat, a model of Type 2 diabetes, which includes insulin resistance, hyperglycemia and obesity. The successful outcome of these studies will provide the foundation for an understanding of the molecular mechanisms underlying the impact of Type 2 diabetes and insulin resistance on cardiac dysfunction. This will facilitate the development of novel therapeutic interventions, designed to close the gap in mortality and morbidity between diabetic and non-diabetic patients with heart disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL067464-04A1
Application #
6920984
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Evans, Frank
Project Start
2000-08-20
Project End
2010-03-31
Budget Start
2005-04-25
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$247,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Marsh, Susan A; Powell, Pamela C; Dell'italia, Louis J et al. (2013) Cardiac O-GlcNAcylation blunts autophagic signaling in the diabetic heart. Life Sci 92:648-56
Medford, H M; Chatham, J C; Marsh, S A (2012) Chronic ingestion of a Western diet increases O-linked-?-N-acetylglucosamine (O-GlcNAc) protein modification in the rat heart. Life Sci 90:883-8
Laczy, Boglárka; Fülöp, Norbert; Onay-Besikci, Arzu et al. (2011) Acute regulation of cardiac metabolism by the hexosamine biosynthesis pathway and protein O-GlcNAcylation. PLoS One 6:e18417
Des Rosiers, Christine; Labarthe, Francois; Lloyd, Steven G et al. (2011) Cardiac anaplerosis in health and disease: food for thought. Cardiovasc Res 90:210-9
Marsh, Susan A; Chatham, John C (2011) The paradoxical world of protein O-GlcNAcylation: a novel effector of cardiovascular (dys)function. Cardiovasc Res 89:487-8
Marsh, Susan A; Dell'Italia, Louis J; Chatham, John C (2011) Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids 40:819-28
Laczy, Boglarka; Marsh, Susan A; Brocks, Charlye A et al. (2010) Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner. Am J Physiol Heart Circ Physiol 299:H1715-27
Chatham, John C; Marchase, Richard B (2010) Protein O-GlcNAcylation: A critical regulator of the cellular response to stress. Curr Signal Transduct Ther 5:49-59
Teo, Chin Fen; Ingale, Sampat; Wolfert, Margreet A et al. (2010) Glycopeptide-specific monoclonal antibodies suggest new roles for O-GlcNAc. Nat Chem Biol 6:338-43
Chatham, John C; Marchase, Richard B (2010) The role of protein O-linked beta-N-acetylglucosamine in mediating cardiac stress responses. Biochim Biophys Acta 1800:57-66

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