Increased levels of misfolded proteins in the heart are associated with a large subset of congestive heart failure (CHF), the final common pathway for virtually all heart diseases and afflicting the life of millions of Americans. Targeted removal of most cellular proteins is primarily done by the ubiquitin-proteasome system (UPS) which degrades a protein via two steps: (1) attachment of a chain of ubiquitin (Ub) to a target protein molecule via a process known as ubiquitination; (2) degradation of the ubiquitinated protein by the proteasome. Cardiac UPS dysfunction is associated with CHF of common causes and a frequently indicated defect is an uncoupling between the two steps, as suggested by the paradoxical co-existence of increased levels of ubiquitinated proteins with elevated or normal proteasomal peptidase activities in diseased myocardium. However, little is known about the molecular basis and pathophysiological significance of the uncoupling. The UBL-UBA family of Ub receptors (Ubiquilin1, Rad23, Ddi1) are purport to recruit ubiquitinated proteins for the proteasome, thereby promoting the coupling. To date, the role of none of these Ub receptors in mammalian hearts is elucidated. Our pilot studies reveal that cardiac Ubqln1 proteins were remarkably increased in human end-stage CHF from ischemic heart disease or dilated cardiomyopathy and in mouse models of desmin-related cardiomyopathy (DRC), a bona fide cardiomyopathy caused by increased expression of misfolded proteins. Our preliminary data also suggest that Ubqln1 promotes proteasomal degradation of ubiquitinated misfolded proteins without altering proteasome activities. Hence, we hypothesize that Ubqln1 up-regulation protects against proteotoxicity in cardiomyocytes by enhancing the recruitment of ubiquitinated misfolded proteins to the proteasome for degradation. A unique set of genetically altered mice as well as human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes will be used to interrogate Ubqln1 and proteasome functions in cardiomyocytes to investigate the role of Ubqln1 in the DRC progression, myocardial ischemia/reperfusion (I/R) injury and post I/R cardiac remodeling in mice and to test the hypothesis that Ubqln1 functions as a shuttling Ub receptor to recruit ubiquitinated misfolded proteins to the proteasome for degradation, thereby protecting against proteotoxicity in cardiomyocytes. The completion of this work is expected to improve our understanding of cardiac protein quality control and provide new molecular targets for developing new strategies to fight cardiac disease with increased proteotoxicity, an increasingly suggested major pathogenic factor of CHF.

Public Health Relevance

Congestive heart failure is the final common pathway of virtually all heart disease and is the most expensive single diagnosis in US health care. It is a highly lethal and disabling syndrome. Despite recent advances in its clinical management, it remains the leading cause of death in the US. This research project will help deepen our understanding on the molecular mechanisms underlying the progression from various primary heart diseases to congestive heart failure, which will ultimately facilitate the search for new measures to prevent or more effectively treat this common and yet life-threatening disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072166-13
Application #
9173463
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2003-07-01
Project End
2018-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of South Dakota
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069
Sane, Sanam; Hafner, Andre; Srinivasan, Rekha et al. (2018) UBXN2A enhances CHIP-mediated proteasomal degradation of oncoprotein mortalin-2 in cancer cells. Mol Oncol 12:1753-1777
Hu, Chengjun; Tian, Yihao; Xu, Hongxin et al. (2018) Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury. J Clin Invest 128:5294-5306
Hou, Ning; Wen, Ying; Yuan, Xun et al. (2017) Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. Exp Mol Pathol 103:267-275
Wang, Xuejun (2017) Vascular Spasm: A Newly Unraveled Cause for Cardiovascular Adversity of Proteasome Inhibition. EBioMedicine 21:51-52
Huang, Hongbiao; Guo, Mingxing; Liu, Ningning et al. (2017) Bilirubin neurotoxicity is associated with proteasome inhibition. Cell Death Dis 8:e2877
Wang, Xuejun; Cui, Taixing (2017) Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy. Am J Physiol Heart Circ Physiol 313:H304-H319
Wu, Penglong; Yuan, Xun; Li, Faqian et al. (2017) Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure. Circ Heart Fail 10:
Abdullah, Ammara; Eyster, Kathleen M; Bjordahl, Travis et al. (2017) Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways. Front Physiol 8:594
Reihe, Casey A; Pekas, Nickolas; Wu, Penglong et al. (2017) Systemic inhibition of neddylation by 3-day MLN4924 treatment regime does not impair autophagic flux in mouse hearts and brains. Am J Cardiovasc Dis 7:134-150
Pan, Bo; Zhang, Hanming; Cui, Taixing et al. (2017) TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux. J Mol Cell Cardiol 113:51-62

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