Heart failure (HF) is poorly treated by current therapies. More knowledge of the deleterious mechanisms that produce this disease is necessary in order to develop novel specific therapies. The focus of this research is on testing therapeutic approaches targeting maladaptive mechanisms that will improve impaired contractility and deficient energy production in HF. Our long-term goal is to identify new highly specific therapeutic targets to treat HF. Our immediate goals are to determine if reducing excessive protein OGlcNAcylation to normal can improve cardiac function in HF. Our preliminary results show that in HF nuclear, cytosolic, sarcoplasmic reticulum (SR) and mitochondrial (Mito) cardiac proteins are excessively OGlcNAcylated. Furthermore, reducing O-GlcNAcylation by transgene expression in mice with HF resulted in improved cardiac function. The hypothesis is that HF-induced abnormalities in cardiac myoc)1:es (CM) can be reverted by expression of specific transgenes that correct the maladaptive excessive protein OGlcNAcylation and/or its deletrious effects on key myocardial proteins. Using viral vector gene transfer in a mouse model of HF, or transgenic mice with HF the following specific goals should be achieved: i) Identify and determine the time course and mechanisms contributing to excessive 0-GlcNAcylation of proteins in the intact CM and in specific organelles of the CM during the evolution of PO-induced HF. 2) Determine if attenuation or reversal of excessive CM protein 0-GlcNAcylation improves function in the failing heart. 3) Establish that excessive 0-GlcNAcylation of specific proteins diminishes Mito function and propagates HF.
In Aim I the mechanisms contributing to excessive protein 0-GlcNAcylation in HF are explored and key cardiac proteins that undergo excessive 0-GlcNAcylation are identified.
Aim I is related to Aim II, in that in Aim II we determine if reversal of excessive nuclear, cytosolic and SR protein 0-GlcNAcylation in CM of HF improves CM and heart function.
Aim III establishes that excessive 0-GlcNAcylation of specific proteins diminishes Mito function.

Public Health Relevance

Heart failure is a significant health problem in the U.S. and is poorly treated by current therapies. Results generated in this study will have a positive impact in our knowledge of the mechanisms that cause heart failure. In addition, therapeutic approaches targeting these novel mechanisms will reveal new potential treatments for this important disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL066941-12
Application #
8743236
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92093
Suarez, Jorge; Cividini, Federico; Scott, Brian T et al. (2018) Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function. J Biol Chem 293:8182-8195
Schilling, Jan M; Head, Brian P; Patel, Hemal H (2018) Caveolins as Regulators of Stress Adaptation. Mol Pharmacol 93:277-285
Giamouridis, Dimosthenis; Gao, Mei Hua; Lai, N Chin et al. (2018) Effects of Urocortin 2 Versus Urocortin 3 Gene Transfer on Left Ventricular Function and Glucose Disposal. JACC Basic Transl Sci 3:249-264
Hastings, Randolph H; Montgrain, Philippe R; Quintana, Rick A et al. (2017) Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression. J Cancer Res Clin Oncol 143:1395-1407
Gao, Mei Hua; Lai, N Chin; Giamouridis, Dimosthenis et al. (2017) Cardiac-directed expression of a catalytically inactive adenylyl cyclase 6 protects the heart from sustained ?-adrenergic stimulation. PLoS One 12:e0181282
Penny, William F; Hammond, H Kirk (2017) Randomized Clinical Trials of Gene Transfer for Heart Failure with Reduced Ejection Fraction. Hum Gene Ther 28:378-384
Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411
Breen, Ellen C; Scadeng, Miriam; Lai, N Chin et al. (2017) Functional magnetic resonance imaging for in vivo quantification of pulmonary hypertension in the Sugen 5416/hypoxia mouse. Exp Physiol 102:347-353
Hammond, H Kirk; Penny, William F; Traverse, Jay H et al. (2016) Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial. JAMA Cardiol 1:163-71
Schilling, Jan M; Patel, Hemal H (2016) Non-canonical roles for caveolin in regulation of membrane repair and mitochondria: implications for stress adaptation with age. J Physiol 594:4581-9

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