Identification of fundamentally cytoprotective pathways in the myocardium lingers as an elusive challenge. Although ischemic preconditioning may be the most powerful experimental cardioprotective strategy known, little clinical application has resulted from its discovery. Based on the premise that transient metabolic alterations occur during ischemic preconditioning, the PI has developed a novel hypothesis wherein activation of a metabolic signal exerts protective effects. Emerging evidence indicates that global increases in levels of a specific serine/threonine post-translational modification, beta-O-linked N-acetylglucosamine (O-GlcNAc), protects cell lines against injury. Here, the PI will attempt to establish this modification as a novel cardiac survival signal and elucidate its potential involvement in myocardial ischemia-reperfusion injury. The general structure of this proposal is designed to answer the questions: What happens to O-GlcNAc levels during ischemia-reperfusion and preconditioning? Is the O-GlcNAc signal sufficient for cardioprotection? What are the target(s) in this process? Does this potentially protective pathway result in chronic improvement in cardiac function? In Specific Aim I (SA I), the applicant will identify temporal changes in O-GlcNAc levels during myocardial ischemia-reperfusion and following ischemic preconditioning. Using complementary pharmacology, adenoviral gene transfer, and RNA interference-mediated translational silencing, the PI will evaluate whether augmentation of O-GlcNAc levels attenuates cardiac injury following in vivo ischemia or in vitro hypoxia-reoxygenation (SA II). Next, the applicant will characterize the downstream targets, namely in the mitochondria (e.g. KATP), of O-GlcNAc-mediated protection using isolated myocytes exposed to hypoxia-reoxygenation and in vivo myocardial ischemia-reperfusion (SA III). Lastly, the PI will ascertain whether acute O-GlcNAc-mediated protection improves long-term cardiac function in vivo following myocardial infarction (SA IV). Data garnered from such innovative studies may establish a novel paradigm in the mechanism of post-ischemic cardiac injury and protection. Possible findings during this project will allow the development of new strategies to combat acute myocardial infarction in patients. LAY SUMMARY: The applicant will focus on a poorly understood metabolic pathway to evaluate the mechanisms of injury during a heart attack. Information gathered from this proposal may help treat heart disease. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL083320-01A1
Application #
7146958
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2006-07-15
Project End
2011-06-30
Budget Start
2006-07-15
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$311,400
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Hosen, Mohammed Rabiul; Militello, Giuseppe; Weirick, Tyler et al. (2018) Airn Regulates Igf2bp2 Translation in Cardiomyocytes. Circ Res 122:1347-1353
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
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
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
Dassanayaka, Sujith; Readnower, Ryan D; Salabei, Joshua K et al. (2015) High glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation. Biochem J 467:115-26
Muthusamy, Senthilkumar; Hong, Kyung U; Dassanayaka, Sujith et al. (2015) E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression. J Biol Chem 290:31013-24
Dassanayaka, Sujith; Jones, Steven P (2015) Recent Developments in Heart Failure. Circ Res 117:e58-63
Brooks, Alan C; DeMartino, Angelica M; Brainard, Robert E et al. (2015) Induction of activating transcription factor 3 limits survival following infarct-induced heart failure in mice. Am J Physiol Heart Circ Physiol 309:H1326-35
Zafir, Ayesha; Bradley, James A; Long, Bethany W et al. (2015) O-GlcNAcylation Negatively Regulates Cardiomyogenic Fate in Adult Mouse Cardiac Mesenchymal Stromal Cells. PLoS One 10:e0142939

Showing the most recent 10 out of 34 publications