Profound derangements in pathophysiology occur during heart failure, including alterations in the cardiomyocyte's ability to coordinate metabolic cues. Glucose represents the quintessential substrate for metabolism. Yet, not all glucose is dedicated to the production of ATP; a fraction of intracellular glucose is shunted into several accessory pathways, such as the Hexosamine Biosynthetic Pathway, which forms the monosaccharide donor for the post-translational modification known as O-linked-?-N-acetylglucosamine (O- GlcNAc). The PI's laboratory has identified O-GlcNAcylation as an important event in the failing heart, and O- GlcNAcase (OGA) is a key regulator of O-GlcNAc removal from targets. Despite significant insights related to the phenomenology of O-GlcNAc in acute myocardial ischemia and heart failure, almost nothing is known about the regulation of the O-GlcNAc enzymes (OGA and OGT) in the heart or other tissues. The present proposal will reduce significantly this critical gap in knowledge. To this end, the present proposal will: i) Identify transcriptional and post-transcriptional regulators of OGA expression; again, nothing is known currently regarding such regulation in the cardiomyocyte. In addition to in vivo studies, experiments will be performed in isolated cells and cell lines using common molecular biology techniques (e.g. promoter mutations, transcription factor binding, transduction). ii) Using a loss-of-function approach, the project will determine the impact of OGA suppression during heart failure. Studies will incorporate tissue-specific, inducible, cre-lox-mediated deletion of the OGA gene in cardiomyocytes. The PI will use genetically modified, surgically operated mice coupled with state-of-the-art physiologic assessment of cardiac function. iii) Mechanistic inquiries will focus on mitochondria to understand how OGA suppression attenuates the severity of heart failure. The PI will perform various analyses of mitochondrial function, including bioenergetics assays, along with protein chemistry to determine how suppression of OGA improves mitochondrial function. The overarching hypothesis holds that that OGA suppression attenuates heart failure through preservation of mitochondrial respiratory integrity. Although not the direct, near-time goal of this project, the results could eventually contribute to new potential treatment options for heart failure, and, because of the potential involvement of O-GlcNAcylation in several diseases, will contribute to new directions in studies of diabetes, Alzheimer's, aging, and vascular diseases.

Public Health Relevance

This project will determine the role of a unique metabolism-related signal in the failing heart. This project will also provide new insights into the molecular regulation of genes also involved in neurodegenerative diseases, diabetes, and other diseases. This project will produce broadly applicable, basic biological insights.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL131647-02
Application #
9281896
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2016-06-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$538,069
Indirect Cost
$187,308
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40208
Hosen, Mohammed Rabiul; Militello, Giuseppe; Weirick, Tyler et al. (2018) Airn Regulates Igf2bp2 Translation in Cardiomyocytes. Circ Res 122:1347-1353
Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A et al. (2018) Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload. Redox Biol 17:440-449
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
Uchida, Shizuka; Jones, Steven P (2018) RNA Editing: Unexplored Opportunities in the Cardiovascular System. Circ Res 122:399-401
Baba, Shahid P; Zhang, Deqing; Singh, Mahavir et al. (2018) Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol 118:183-192
Gibb, Andrew A; Epstein, Paul N; Uchida, Shizuka et al. (2017) Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth. Circulation 136:2144-2157
Jones, Steven P (2017) I'll Have the Rigor, but Hold the Mortis. Circ Res 120:1852-1854
Dassanayaka, Sujith; Brainard, Robert E; Watson, Lewis J et al. (2017) Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy. Basic Res Cardiol 112:23
Zucker, Irving H; Lindsey, Merry L; Delmar, Mario et al. (2017) Why publish in the American Journal of Physiology-Heart and Circulatory Physiology? Am J Physiol Heart Circ Physiol 313:H221-H223
Kingery, Justin R; Hamid, Tariq; Lewis, Robert K et al. (2017) Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol 112:19

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