Myocyte signaling and the response to stress

Summary

Principal Investigator: C Patterson
Abstract: DESCRIPTION (provided by applicant): Changes in cardiomyocyte size occur in a variety of clinical scenarios, including pressure overload, myocardial infarction, metabolic stress, and in some genetic conditions. Although much is now known about the signaling pathways that cause cardiomyocytes to hypertrophy, much less is known about the pathways that inhibit or reverse hypertrophy, nor do we understand how cardiomyocytes atrophy in conditions such as dilated cardiomyopathy. At the molecular level, almost nothing is known about how cardiac proteins such as sarcomere components are removed to accommodate reductions in cell size. These unanswered questions represent a major gap in our understanding of the pathophysiology of cardiovascular disease. Our laboratory has recently identified 2 ubiquitin ligases, atrogin and MuRF1 (muscle ring-finger protein 1), that are responsible for antagonizing cardiomyocyte signaling in the setting of hypertrophic stress, in part through targeted degradation of cardiomyocyte signaling and structural proteins. These proteins therefore provides ideal models for understanding how cardiomyocytes adapt to stress and how cell size is regulated and maintained in pathophysiologic circumstances. We hypothesize that cardiac-specific ubiquitin ligases play key roles in antagonizing cardiomyocyte signaling pathways that provoke hypertrophy, and regulate adaptive responses in the setting of cardiomyocyte stress. Knowledge of the regulation of these proteins and how they affect specific signaling events and choose targets for ubiquitylation will provide a new level of understanding of how the heart responds to clinically relevant insults. To test these hypotheses, we propose a combined biochemical, cellular, genetic, and physiologic approach 1) to characterize the cellular relationships between atrogin and cardiac growth pathways in mediating responses to stress;2) To assess the molecular and cellular roles of MuRF family proteins in cardiomyocyte stress responses;and 3) To contrast the roles of MuRFs 1-3 in pathophysiologic cardiac responses. In addition to providing a new basis to appreciate the role of targeted protein turnover as a key regulatory mechanism in cardiomyocyte biology, these studies will help us to predict whether these proteins represent new potential targets for intervention in diseases associated with abnormal regulation of cardiomyocyte volume.
Funding Period: 2000-06-01 - 2010-05-31
more information: NIH RePORT

Top Publications

  1. pmc The role of ubiquitin ligases in cardiac disease
    Monte S Willis
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA Electronic address
    J Mol Cell Cardiol 71:43-53. 2014
  2. pmc Muscle ring finger 1 and muscle ring finger 2 are necessary but functionally redundant during developmental cardiac growth and regulate E2F1-mediated gene expression in vivo
    Monte S Willis
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
    Cell Biochem Funct 32:39-50. 2014
  3. pmc The ubiquitin-proteasome system and cardiovascular disease
    Saul R Powell
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA
    Prog Mol Biol Transl Sci 109:295-346. 2012
  4. pmc Recovery from decompensated heart failure is associated with a distinct, phase-dependent gene expression profile
    Nancy M Andersen
    Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA
    J Surg Res 178:72-80. 2012
  5. ncbi ERK signaling is a central regulator for BMP-4 dependent capillary sprouting
    Qian Zhou
    Department of Cardiology, University of Freiburg, Freiburg, Germany
    Cardiovasc Res 76:390-9. 2007
  6. pmc Tearin' up my heart: proteolysis in the cardiac sarcomere
    Andrea L Portbury
    McAllister Heart Institute, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599 7126, USA
    J Biol Chem 286:9929-34. 2011
  7. pmc Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease
    Monte S Willis
    Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599 7126, USA
    Circ Res 106:463-78. 2010
  8. pmc Cardiac muscle ring finger-1--friend or foe?
    Monte S Willis
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599 7126, USA
    Trends Cardiovasc Med 20:12-6. 2010
  9. pmc Recombinant human interleukin-11 treatment enhances collateral vessel growth after femoral artery ligation
    Julius Aitsebaomo
    McAllister Heart Institute, University of North Carolina, 103 Mason Farm Rd, Chapel Hill, NC 27599 7126, USA
    Arterioscler Thromb Vasc Biol 31:306-12. 2011
  10. pmc Regulation of AMPK by the ubiquitin proteasome system
    Makhosazane Zungu
    Discipline of Human Physiology, University of KwaZulu Natal, Durban, South Africa
    Am J Pathol 178:4-11. 2011

Scientific Experts

  • C Patterson
  • Julius Aitsebaomo
  • Martin Moser
  • Hui Hua Li
  • Monte S Willis
  • Sarah M Ronnebaum
  • Andrea L Portbury
  • Saul R Powell
  • Nancy M Andersen
  • Makhosazane Zungu
  • Ping Xie
  • Shu Bing Qian
  • Jin Na Min
  • Xinchun Pi
  • Jonathon W Homeister
  • Qian Zhou
  • R Kelley
  • Malia B Potts
  • Chunlian Zhang
  • J E Ferguson
  • Mauricio Rojas
  • Amir Lerman
  • Craig H Selzman
  • Joerg Herrmann
  • Xuejun Wang
  • Ru Hang Tang
  • William E Stansfield
  • M Faadiel Essop
  • Jonathan C Schisler
  • Chris McCudden
  • Lauren Waldron
  • Walter J Chazin
  • Rachel E Klevit
  • Mingpeng She
  • Dongfeng Gu
  • Hua Zhang
  • Yongna Fan
  • Neelima Choudhary
  • Yuan Zhang
  • Ryan A Whaley
  • Norman E Sharpless
  • Pamela Lockyer
  • Tobias Krauss
  • Stephan Winnik
  • Alberto Vargas
  • Christoph Bode
  • Jennifer Heinke
  • Mohanish Deshmukh
  • Allyson E Vaughn
  • Lloyd H Michael
  • Holly McDonough
  • Xiao Rui He
  • Rusty W Kelley
  • Zhelong Xu

Detail Information

Publications33

  1. pmc The role of ubiquitin ligases in cardiac disease
    Monte S Willis
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA Electronic address
    J Mol Cell Cardiol 71:43-53. 2014
    ..This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy". ..
  2. pmc Muscle ring finger 1 and muscle ring finger 2 are necessary but functionally redundant during developmental cardiac growth and regulate E2F1-mediated gene expression in vivo
    Monte S Willis
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
    Cell Biochem Funct 32:39-50. 2014
    ..We recently reported that MuRF1, but not MuRF2, regulates pathologic cardiac hypertrophy in vivo. This was surprising given that MuRF1 and MuRF2 interact with each other and many of the same sarcomeric proteins experimentally...
  3. pmc The ubiquitin-proteasome system and cardiovascular disease
    Saul R Powell
    Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA
    Prog Mol Biol Transl Sci 109:295-346. 2012
    ..Furthering our knowledge of this system may help in the development of new UPS-based therapeutic modalities for mitigation of cardiovascular disease...
  4. pmc Recovery from decompensated heart failure is associated with a distinct, phase-dependent gene expression profile
    Nancy M Andersen
    Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA
    J Surg Res 178:72-80. 2012
    ..We hypothesize that the pathways involved with myocardial recovery are not simply the reverse of those that cause heart failure. However, determining when and how a decompensated heart can recover remains unknown...
  5. ncbi ERK signaling is a central regulator for BMP-4 dependent capillary sprouting
    Qian Zhou
    Department of Cardiology, University of Freiburg, Freiburg, Germany
    Cardiovasc Res 76:390-9. 2007
    ....
  6. pmc Tearin' up my heart: proteolysis in the cardiac sarcomere
    Andrea L Portbury
    McAllister Heart Institute, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599 7126, USA
    J Biol Chem 286:9929-34. 2011
    ..This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere...
  7. pmc Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease
    Monte S Willis
    Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599 7126, USA
    Circ Res 106:463-78. 2010
    ..In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease...
  8. pmc Cardiac muscle ring finger-1--friend or foe?
    Monte S Willis
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599 7126, USA
    Trends Cardiovasc Med 20:12-6. 2010
    ....
  9. pmc Recombinant human interleukin-11 treatment enhances collateral vessel growth after femoral artery ligation
    Julius Aitsebaomo
    McAllister Heart Institute, University of North Carolina, 103 Mason Farm Rd, Chapel Hill, NC 27599 7126, USA
    Arterioscler Thromb Vasc Biol 31:306-12. 2011
    ....
  10. pmc Regulation of AMPK by the ubiquitin proteasome system
    Makhosazane Zungu
    Discipline of Human Physiology, University of KwaZulu Natal, Durban, South Africa
    Am J Pathol 178:4-11. 2011
    ..The relevance of AMPK ubiquitination in cardiac disease has yet to be tested directly, but it likely represents an important mechanism that occurs in common cardiac diseases that may be targeted for therapy...
  11. pmc Tear me down: role of calpain in the development of cardiac ventricular hypertrophy
    Cam Patterson
    McAllister Heart Institute, University of North Carolina at Chapel Hill, 27599 7525, USA
    Circ Res 109:453-62. 2011
    ..The context within which calpain inhibition might be developed for therapeutic intervention of cardiac hypertrophy is then discussed...
  12. pmc The FoxO family in cardiac function and dysfunction
    Sarah M Ronnebaum
    McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
    Annu Rev Physiol 72:81-94. 2010
    ..In this review, we discuss the mechanisms of FoxO regulation and outcomes of FoxO signaling under normal and pathological cardiovascular contexts...
  13. pmc Engineering a ubiquitin ligase reveals conformational flexibility required for ubiquitin transfer
    Shu Bing Qian
    Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA
    J Biol Chem 284:26797-802. 2009
    ..Our results not only reveal conformational changes of E3 during ubiquitin transfer but also provide a promising approach to custom-made E3 for targeted proteolysis...
  14. pmc Cardiac muscle ring finger-1 increases susceptibility to heart failure in vivo
    Monte S Willis
    Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, 27599 7525, USA
    Circ Res 105:80-8. 2009
    ..This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo...
  15. pmc CHIP represses myocardin-induced smooth muscle cell differentiation via ubiquitin-mediated proteasomal degradation
    Ping Xie
    Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, China
    Mol Cell Biol 29:2398-408. 2009
    ....
  16. pmc Build it up-Tear it down: protein quality control in the cardiac sarcomere
    Monte S Willis
    Carolina Cardiovascular Biology Center, University of North Carolina, 8200 Medical Biomolecular Research Bldg, 103 Mason Farm Road, Chapel Hill, NC 27599 7126, USA
    Cardiovasc Res 81:439-48. 2009
    ..In this review, we highlight the dynamic interplay between sarcomere-specific chaperones and ubiquitin-dependent degradation of sarcomere proteins that is necessary in order to maintain structure and function of the cardiac sarcomere...
  17. pmc Zinc fingers in the pizza pie aorta
    Jonathon W Homeister
    Circ Res 103:687-9. 2008
  18. ncbi Mechanisms of endothelial differentiation in embryonic vasculogenesis
    J E Ferguson
    Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599 7126, USA
    Arterioscler Thromb Vasc Biol 25:2246-54. 2005
    ....
  19. ncbi Even flow: shear cues vascular development
    Cam Patterson
    Arterioscler Thromb Vasc Biol 25:1761-2. 2005
  20. pmc Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP
    Malia B Potts
    Neuroscience Center, Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Cell Biol 171:925-30. 2005
    ..These data identify an important function of XIAP in cardiomyocytes and point to a striking similarity in the regulation of apoptosis in postmitotic cells...
  21. ncbi A salty salute: progenitor cell therapies and no-option heart disease
    Cam Patterson
    Am Heart J 151:553-5. 2006
  22. ncbi Search and destroy: the role of protein quality control in maintaining cardiac function
    Cam Patterson
    J Mol Cell Cardiol 40:438-41. 2006
  23. ncbi Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling
    Cam Patterson
    Division of Cardiology and Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599 7126, USA
    Arterioscler Thromb Vasc Biol 26:1473-80. 2006
    ..However, the optimal payloads for stents are not clear, and the appropriate stent-based therapies for high-risk patients, such as diabetics, have not been clearly established...
  24. ncbi Slice me nice: DNAzymes get close to the heart
    R Kelley
    Department of Medicine, Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 275099 7126, USA
    J Thromb Haemost 4:1476-8. 2006
  25. ncbi Into the heart: the emerging role of the ubiquitin-proteasome system
    Monte S Willis
    Carolina Cardiovascular Biology Center, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599 7126, USA
    J Mol Cell Cardiol 41:567-79. 2006
    ..g. ubiquitin, E1, E2, E3, proteasome) are themselves transcriptionally regulated in cardiac disease. Our understanding of the precise nature by which the UPS regulates key biological functions in cardiac disease has just begun...
  26. pmc Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo
    Monte S Willis
    Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599 7126, USA
    Circ Res 100:456-9. 2007
    ..These studies describe for the first time distinct and nonoverlapping functional characteristics of MuRF1 and MuRF2 in response to cardiac stress in vivo...
  27. ncbi The bitter end: the ubiquitin-proteasome system and cardiac dysfunction
    Cam Patterson
    Division of Cardiology and Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599 7126, USA
    Circulation 115:1456-63. 2007
    ..This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms...
  28. pmc BMPER is a conserved regulator of hematopoietic and vascular development in zebrafish
    Martin Moser
    University of Freiburg, Internal Medicine III, Hugstetter Strasse 55, 79106 Freiburg, Germany
    J Mol Cell Cardiol 43:243-53. 2007
    ..The generation of the caudal vein is compromised and the pattern guiding of the intersomitic vessels is disturbed, indicating that zbmper is required for early steps in vascular pattern formation and hematopoiesis in zebrafish...
  29. pmc Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins
    Hui Hua Li
    Carolina Cardiovascular Biology Center, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 7126, USA
    J Clin Invest 117:3211-23. 2007
    ....
  30. ncbi Twin layers of lightning: a new role for the chaperone Hsp90 in angiogenesis
    Xinchun Pi
    Arterioscler Thromb Vasc Biol 28:6-7. 2008
  31. pmc CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control
    Jin Na Min
    Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599 7126, USA
    Mol Cell Biol 28:4018-25. 2008
    ..Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo...
  32. ncbi CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice
    Chunlian Zhang
    Carolina Cardiovascular Biology Center, Univ of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Bldg, Chapel Hill, NC 27599 7126, USA
    Am J Physiol Heart Circ Physiol 288:H2836-42. 2005
    ..Quality control mechanisms therefore may be underappreciated clinical targets for maximizing myocardial protection after injury...