It is well established that diabetes leads to a marked increased risk for the development of heart failure independent of other risk factors;however, there is no consensus as to the mechanisms involved or the most appropriate treatment strategies. The O-linked attachment of ss-N-acetyl- glucosamine (O-GlcNAc) to serine and threonine residues is a highly dynamic post-translational modification of nuclear and cytoplasmic proteins. This novel, metabolically regulated signaling pathway is emerging as a key regulator of critical biological processes and sustained increases in O-GlcNAcylation have been linked to the cardiovascular complications associated with diabetes. Conversely, recent studies have shown that acute activation of O-GlcNAc levels protects against hypoxic and ischemic stress. However, despite our increasing appreciation for the significance of O-GlcNAcylation in mediating the response of cardiomyocytes to acute and chronic stress, little is known regarding the fundamental role of O-GlcNAcylation in regulating normal cardiomyocyte function. Therefore, based on our preliminary studies the goal of this proposal is to test the following hypotheses: 1) In the normal heart protein O-GlcNAcylation contributes to regulation of cardiomyocyte gene expression, metabolism and autophagy and 2) Dysregulation in O-GlcNAc synthesis and degradation contribute to the adverse effects of diabetes on the heart including altered gene expression, metabolic dysfunction and impaired autophagic response. Thus the aims of this proposal are to determine the role of O-GlcNAcylation in: 1) The regulation of cardiomyocyte gene expression and e how this is altered in response to type-2 diabetes and identify O-GlcNAc modified cardiomyocyte proteins that are susceptible to acute and chronic changes in O-GlcNAc levels;2) Acute and chronic regulation of cardiac metabolism and identify the metabolic factors involved in regulating O- GlcNAc turnover in hearts from normal and type-2 diabetic mice;3) Mediating the balance between cardiomyocyte autophagy and apoptosis in normal and type-2 diabetic cardiomyocytes. The successful completion of the studies outlined in this proposal will significantly enhance our understanding of the impact of this novel metabolically mediated signaling pathway on the cardiomyocyte function under normal conditions as well as how dysregulation in protein O- GlcNAcylation contributes to adverse effects of diabetes on the heart. Consequently, the outcome of this application will be novel mechanistic insights regarding the influence of protein O-GlcNAcylation on myocardial physiology and pathophysiology, potentially identifying novel therapeutic targets.

Public Health Relevance

Although the there have been tremendous advances in treatment of cardiovascular disease;diabetic patients remain at substantially increased risk in for developing heart failure and dying from cardiac disease than non-diabetic patients. The overall goal of this project is to examine how changes in a newly identified modification of proteins, which is regulated in large part by glucose metabolism, affects the function of heart cells also known as cardiomyocytes. The outcome of this project will provide new insights into the detrimental effects of diabetes on the heart, potentially identifying of new approaches for treating diabetic patients with heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101192-04
Application #
8479421
Study Section
Special Emphasis Panel (ZRG1-CVRS-F (02))
Program Officer
Wong, Renee P
Project Start
2010-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$345,183
Indirect Cost
$109,563
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Heath, Jack M; Sun, Yong; Yuan, Kaiyu et al. (2014) Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus. Circ Res 114:1094-102
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
Chatham, John C; Young, Martin E (2013) Regulation of myocardial metabolism by the cardiomyocyte circadian clock. J Mol Cell Cardiol 55:139-46
McLarty, Jennifer L; Marsh, Susan A; Chatham, John C (2013) Post-translational protein modification by O-linked N-acetyl-glucosamine: its role in mediating the adverse effects of diabetes on the heart. Life Sci 92:621-7
Collins, Helen E; Zhu-Mauldin, Xiaoyuan; Marchase, Richard B et al. (2013) STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305:H446-58
Lauzier, Benjamin; Vaillant, Fanny; Merlen, Clemence et al. (2013) Metabolic effects of glutamine on the heart: anaplerosis versus the hexosamine biosynthetic pathway. J Mol Cell Cardiol 55:92-100
Darley-Usmar, Victor M; Ball, Lauren E; Chatham, John C (2012) Protein O-linked *-N-acetylglucosamine: a novel effector of cardiomyocyte metabolism and function. J Mol Cell Cardiol 52:538-49
Laczy, Boglarka; Fulop, 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
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
Durgan, David J; Pat, Betty M; Laczy, Boglarka et al. (2011) O-GlcNAcylation, novel post-translational modification linking myocardial metabolism and cardiomyocyte circadian clock. J Biol Chem 286:44606-19

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