Posttranslational modification by ubiquitin and ubiquitin-like protein is essential for protein quality control. Defects in ubiquitin-mediated proteolysis are pathogenic to various cardiac diseases including desmin-related cardiomyopathy (DRC) and myocardial ischemia reperfusion (I/R) injury. However, little is known about the importance of ubiquitin-like proteins such as NEDD8 in cardiac myocytes (CM) physiology and pathophysiology. Preliminary data in this application reveal a novel and underappreciated role of NEDD8 in the CM and form the basis of our long-term goal: to understand how NEDD8 signaling can be modulated to regulate CM function and ultimately cardiac disease. Conjugation or deconjugation of NEDD8 to target proteins (neddylation or deneddylation) is dynamically regulated by a family of enzymes. Neddylation regulates a variety of essential cellular processes including proteolysis. Our preliminary data reveal a striking increase of neddylated proteins in the hearts from animal models of cardiac diseases, as well as in human failing hearts with ischemic or dilated cardiomyopathy. The buildup of neddylated proteins is functionally significant, as the mice deficient of a NEDD8 deconjuation enzyme develop severe cardiomyopathy through impairing proteolysis. Attenuation of neddylation by multiple means protects CMs from cell injury. These findings collectively indicate that the excessive neddylated proteins impairs proteolysis and are toxic to CMs, and that strategies to prevent/normalize neddylated proteins promote CM survival and function. NUB1L is a negative regulator of neddylation. NUB1L expression reduces neddylated proteins, enhances proteasomal function, and prevents stress-induced CM cell death. Therefore, the goal of the current project is to define the role of NUB1L in regulation of neddylation and protein degradation in the heart. We will test our central hypothesis that NUB1L reduces neddylated proteins and protects the heart against proteotoxic stress.
Aim 1 will determine how NUB1L regulates neddylation and the impact of diminished neddylation on cardiac structure and function, using a novel transgenic mouse model.
Aim 2 will test whether NUB1L expression enhances cardiac proteasomal function using a transgenic reporter, and determine whether suppression of neddylation regulates the removal of misfolded proteins in the heart and alters DRC progression.
Aim 3 will determine the efficacy of suppression of neddylation, by both pharmacologic inhibitor and NUB1L expression, on myocardial I/R injury. Strategies to reduce neddylation may be effective therapeutic strategies to treat DRC and ischemic cardiomyopathy. The translational outcomes of this proposal include the preservation of muscle in myocardial infarction and prevention of heart failure, key missions of the NIH. The proposed studies are the first to target protein neddylation in models of cardiac diseases and will employ an innovative approach using genetically modified mice and pharmacologic intervention.

Public Health Relevance

Heart failure resulting from cardiovascular disease is the leading cause of death in the U.S. and other industrialized nations. The proposed research is relevant to the National Institute of Health's mission because these studies will lead to a better understanding and advance knowledge in the development of a genetically inheritable heart disease and also in the myocardial ischemia/reperfusion injury field, by new discoveries of mechanisms by which endogenous factors protect the heart. This research will potentially lead to the development of new drug therapies for treating patients with acute myocardial infarction. This research will also increase our understanding of the biology of neddylation in the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL124248-04
Application #
9312309
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Augusta University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Li, Jie; Ma, Wenxia; Yue, Guihua et al. (2017) Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy. J Mol Cell Cardiol 102:53-60
Liu, Jinbao; Su, Huabo; Wang, Xuejun (2016) The COP9 signalosome coerces autophagy and the ubiquitin-proteasome system to police the heart. Autophagy 12:601-2
Li, Lei; Cao, Yu; Wu, Haitao et al. (2016) Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation. Neuron 92:1007-1019
Bayoumi, Ahmed S; Sayed, Amer; Broskova, Zuzana et al. (2016) Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease. Int J Mol Sci 17:356
Park, Kyoung-Mi; Teoh, Jian-Peng; Wang, Yongchao et al. (2016) Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 311:H371-83
Lucas, Rudolf; Yue, Qiang; Alli, Abdel et al. (2016) The Lectin-like Domain of TNF Increases ENaC Open Probability through a Novel Site at the Interface between the Second Transmembrane and C-terminal Domains of the ?-Subunit. J Biol Chem 291:23440-23451
Archer, Krystal; Broskova, Zuzana; Bayoumi, Ahmed S et al. (2015) Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases. Int J Mol Sci 16:23651-67
Tang, Yaoping; Wang, Yongchao; Park, Kyoung-Mi et al. (2015) MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death. Cardiovasc Res 106:387-97
Li, Jie; Johnson, John A; Su, Huabo (2015) Ubiquitin and ubiquitin-like proteins in cardiac disease and protection. Curr Drug Targets :
Su, Huabo; Li, Jie; Zhang, Hanming et al. (2015) COP9 signalosome controls the degradation of cytosolic misfolded proteins and protects against cardiac proteotoxicity. Circ Res 117:956-66

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