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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Veterans Medical Research Fdn/San Diego
San Diego
United States
Zip Code
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
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
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
Gao, Mei Hua; Giamouridis, Dimosthenis; Lai, N Chin et al. (2016) One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance. JCI Insight 1:e88322
Miyanohara, Atsushi; Kamizato, Kota; Juhas, Stefan et al. (2016) Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs. Mol Ther Methods Clin Dev 3:16046
Chen, Chao; Li, Ruixia; Ross, Robert S et al. (2016) Integrins and integrin-related proteins in cardiac fibrosis. J Mol Cell Cardiol 93:162-74
Kassan, Adam; Pham, Uyen; Nguyen, Quynhmy et al. (2016) Caveolin-3 plays a critical role in autophagy after ischemia-reperfusion. Am J Physiol Cell Physiol 311:C854-C865
Cividini, Federico; Scott, Brian T; Dai, Anzhi et al. (2016) O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts. J Biol Chem 291:26515-26528

Showing the most recent 10 out of 103 publications