Despite improvements in the management of patients with coronary heart disease there is a growing need for the development of new treatments that can be administered not only in response to an acute myocardial infarction, but also prior to surgery. Recently, increased levels of N-acetylglucosamine (0-GlcNAc) on cytoplasmic and nuclear proteins have been linked to improved cell survival in response to stress. Our preliminary data demonstrate for the first time that in the heart, increased protein O-GlcNAcylation resulting from glucosamine treatment is protective in response to ischemia/ reperfusion. We also show that protection associated with hyperglycemia and glutamine may be mediated via the same pathways. Therefore, we propose that increased flux through the hexosamine biosynthesis pathway decreases myocyte injury resulting from ischemia/reperfusion by promoting elevated levels of protein-associated O-GlcNAc thereby leading to improved cellular recovery. Consequently, the aims of this proposal are: 1) Demonstrate that ischemic protection resulting from glucosamine treatment is mediated by protein O- GlcNAcylation;2) Determine whether other metabolic interventions that lead to ischemic protection do so because of increased protein O-GlcNAcylation;3) Determine whether signaling pathways such as phosphatidylinositol-3-OH kinase (PI3K), mitogen activated protein kinase (MARK) and protein kinase C (PKC) that have been shown to be modulated in response to increased HBP flux as well as implicated in ischemic cardioprotection, also mediate glucosamine-induced cardioprotection;4) Identify cardiac proteins that are targets for O-GlcNAcylation resulting from glucosamine treatment that may be involved in glucosamine-induced cardioprotection. Experiments will be performed using the isolated perfused rat heart and cultured neonatal rat ventricular myocytes. We will use NMR isotopomer analysis in combination with cellular, molecular and proteomic techniques to evaluate the effect of acute glucosamine treatment on the heart and to elucidate its cardioprotective mechanisms. The number of people suffering from acute myocardial infarction and its subsequent complications continues to increase. The successful outcome of this proposal will identify novel targets for the development of new therapeutic agents for the treatment and management of patients with ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079364-05
Application #
7789653
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2006-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$413,266
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
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
Chatham, John C; Young, Martin E (2013) Regulation of myocardial metabolism by the cardiomyocyte circadian clock. J Mol Cell Cardiol 55:139-46
Hilgers, Rob H P; Xing, Dongqi; Gong, Kaizheng et al. (2012) Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction. Am J Physiol Heart Circ Physiol 303:H513-22
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
Zou, Luyun; Zhu-Mauldin, Xiaoyuan; Marchase, Richard B et al. (2012) Glucose deprivation-induced increase in protein O-GlcNAcylation in cardiomyocytes is calcium-dependent. J Biol Chem 287:34419-31
Dranka, Brian P; Benavides, Gloria A; Diers, Anne R et al. (2011) Assessing bioenergetic function in response to oxidative stress by metabolic profiling. Free Radic Biol Med 51:1621-35
Xing, Dongqi; Gong, Kaizheng; Feng, Wenguang et al. (2011) O-GlcNAc modification of NF?B p65 inhibits TNF-?-induced inflammatory mediator expression in rat aortic smooth muscle cells. PLoS One 6:e24021
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
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
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

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