Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation

Summary

Principal Investigator: David M Warshaw
Abstract: Mutations in cardiac myosin binding protein-C (cMyBP-C) lead to sudden death in young individuals with Familial Hypertrophic Cardiomyopathy. Despite Its clinical importance and its association with the actomyosin molecular motor of the heart, a significant gap still remains in understanding how cMyBP-C modulates cardiac power production. In addition, cMyBP-C is phosphorylated following p-adrenergic stimulation, suggesting that cMyBP-C Itself may be regulated in a phosphorylation-dependent manner. This Program Project (3 projects and 3 cores) will provide a comprehensive molecular understanding of cMyBP-C function, its regulation by phosphorylation, and its impact on cardiac contractility. Using state-ofthe- art techniques, we will characterize cMyBP-C's structure and function through studies ranging from the mechanics of the whole heart down to interactions between a single cMyBP-C molecule and the actomyosin molecular motor. Project #1 will use high resolution 3-dimensional electron microscopic reconstruction to characterize the structure of cMyBP-C and its sarcomeric organization, providing insight to its functional capacity. Project #2 will use the laser trap to assess cMyBP-C's ability to modulate actomyosin power production at the single molecule level, while Project #3 will use transgenic mouse models to define the role of cMyBP-C's putative actin-binding and its phosphorylation on cardiac function under various physiological conditions. The Ventricular and Cardiac Fiber Characterization and Integration Core (Core B) will gather the ventricular performance and fiber mechanical data to bridge the physiological gap between the single molecule and whole animal studies. In addition, the Core will provide a modeling platform to integrate the data from all physiological levels into a mechanistic model of cMyBP-C functionality. The Mouse and cMyBP-C Protein Production Core (Core C) will generate mice with mutant cMyBP-C and in vitro expression of mutant cMyBP-C protein at its actin-binding and phosphorylation domains. These hearts and protein will be studied at all anatomical levels by the various projects. The Program Project's long term goals are to: 1) define cMyBP-C's molecular structure and sarcomeric organization;2) determine how cMyBP-C modulates cardiac function in a phosphorylation-dependent manner;3) define why alterations in cMyBP-C phosphorylation are associated with heart failure in humans.
Funding Period: 2000-02-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation Novel mechanism of cardiac stress modulation by PDE5 inhibition
    Norimichi Koitabashi
    Division of Cardiology, Ross 858, Department of Medicine, Johns Hopkins University Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA
    J Mol Cell Cardiol 48:713-24. 2010
  2. pmc Distribution of myosin attachment times predicted from viscoelastic mechanics of striated muscle
    Bradley M Palmer
    Department of Molecular Physiology and Biophysics, University of Vermont, 122 HSRF, Beaumont Avenue, Burlington, VT 05405, USA
    J Biomed Biotechnol 2011:592343. 2011
  3. pmc Atg7 induces basal autophagy and rescues autophagic deficiency in CryABR120G cardiomyocytes
    J Scott Pattison
    Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Circ Res 109:151-60. 2011
  4. pmc Full-length myosin Va exhibits altered gating during processive movement on actin
    Jessica M Armstrong
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Proc Natl Acad Sci U S A 109:E218-24. 2012
  5. pmc The extent of cardiac myosin binding protein-C phosphorylation modulates actomyosin function in a graded manner
    Abbey E Weith
    Department of Molecular Physiology and Biophysics, University of Vermont, HSRF, Room 116, 149 Beaumont Ave, Burlington, VT 05405, USA
    J Muscle Res Cell Motil 33:449-59. 2012
  6. pmc Mechanical coupling between myosin molecules causes differences between ensemble and single-molecule measurements
    Sam Walcott
    Department of Mathematics, University of California, Davis, California, USA
    Biophys J 103:501-10. 2012
  7. pmc Determination of the critical residues responsible for cardiac myosin binding protein C's interactions
    Md Shenuarin Bhuiyan
    J Mol Cell Cardiol 53:838-47. 2012
  8. pmc A branched kinetic scheme describes the mechanochemical coupling of Myosin Va processivity in response to substrate
    Chong Zhang
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA
    Biophys J 103:728-37. 2012
  9. pmc Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor
    Jeffrey R Moore
    Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA
    Circ Res 111:375-85. 2012
  10. pmc Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain
    Abbey Weith
    Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    J Mol Cell Cardiol 52:219-27. 2012

Research Grants

  1. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013

Detail Information

Publications101 found, 100 shown here

  1. pmc Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation Novel mechanism of cardiac stress modulation by PDE5 inhibition
    Norimichi Koitabashi
    Division of Cardiology, Ross 858, Department of Medicine, Johns Hopkins University Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA
    J Mol Cell Cardiol 48:713-24. 2010
    ..Thus PDE5-inhibition blocks TRPC6 channel activation and associated Cn/NFAT activation signaling by PKG-dependent channel phosphorylation...
  2. pmc Distribution of myosin attachment times predicted from viscoelastic mechanics of striated muscle
    Bradley M Palmer
    Department of Molecular Physiology and Biophysics, University of Vermont, 122 HSRF, Beaumont Avenue, Burlington, VT 05405, USA
    J Biomed Biotechnol 2011:592343. 2011
    ....
  3. pmc Atg7 induces basal autophagy and rescues autophagic deficiency in CryABR120G cardiomyocytes
    J Scott Pattison
    Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Circ Res 109:151-60. 2011
    ..Impaired autophagic function is a potential cause of misfolded protein accumulations, cytoplasmic aggregate loads, and cardiac disease. Atg7, a mediator of autophagosomal biogenesis, is a putative regulator of autophagic function...
  4. pmc Full-length myosin Va exhibits altered gating during processive movement on actin
    Jessica M Armstrong
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Proc Natl Acad Sci U S A 109:E218-24. 2012
    ..This unique mechanical state may be an intermediate in the pathway between the inhibited and active states of the motor...
  5. pmc The extent of cardiac myosin binding protein-C phosphorylation modulates actomyosin function in a graded manner
    Abbey E Weith
    Department of Molecular Physiology and Biophysics, University of Vermont, HSRF, Room 116, 149 Beaumont Ave, Burlington, VT 05405, USA
    J Muscle Res Cell Motil 33:449-59. 2012
    ..This study suggests that increasing phosphorylation of cMyBP-C incrementally reduces its modulation of actomyosin motion generation providing a tunable mechanism to regulate cardiac function...
  6. pmc Mechanical coupling between myosin molecules causes differences between ensemble and single-molecule measurements
    Sam Walcott
    Department of Mathematics, University of California, Davis, California, USA
    Biophys J 103:501-10. 2012
    ..This ensemble-size effect challenges the simple detachment limited model of motility, because even when motility speed is limited by ADP release, increasing attachment rate can increase motility speed...
  7. pmc Determination of the critical residues responsible for cardiac myosin binding protein C's interactions
    Md Shenuarin Bhuiyan
    J Mol Cell Cardiol 53:838-47. 2012
    ....
  8. pmc A branched kinetic scheme describes the mechanochemical coupling of Myosin Va processivity in response to substrate
    Chong Zhang
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA
    Biophys J 103:728-37. 2012
    ..This has uncovered states not normally sampled by the motor, and suggests that every transition involving substrate binding and release may be strain-dependent...
  9. pmc Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor
    Jeffrey R Moore
    Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA
    Circ Res 111:375-85. 2012
    ....
  10. pmc Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain
    Abbey Weith
    Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    J Mol Cell Cardiol 52:219-27. 2012
    ..e. by imposing an effective viscous load within the sarcomere...
  11. pmc Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle
    Oscar H Cingolani
    Division of Cardiology, Department of Medicine, Department of Biomedical Engineering, The Johns Hopkins University Medical Institutions, Baltimore, MD 21205, USA
    Circ Res 109:1410-4. 2011
    ..Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism...
  12. pmc Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload
    Norimichi Koitabashi
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA
    J Clin Invest 121:2301-12. 2011
    ..Thus, myocyte targeting is required to modulate TGF-β in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction...
  13. pmc Single Qdot-labeled glycosylase molecules use a wedge amino acid to probe for lesions while scanning along DNA
    Andrew R Dunn
    The Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA
    Nucleic Acids Res 39:7487-98. 2011
    ..The search mechanism for an Fpg variant, F111A, lacking a phenylalanine wedge residue no longer displayed slow, sub-diffusive motion compared to wild type, suggesting that Fpg base interrogation may be accomplished by Phe(111) insertion...
  14. pmc Simultaneous observation of tail and head movements of myosin V during processive motion
    Hailong Lu
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405, USA
    J Biol Chem 285:42068-74. 2010
    ..Back stepping may provide a mechanism to ensure efficient cargo delivery even when myoV encounters obstacles within the actin cytoskeletal meshwork or when other motors are attached to the same cargo...
  15. pmc Signaling and myosin-binding protein C
    Jeanne James
    Department of Pediatrics and the Heart Institute, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    J Biol Chem 286:9913-9. 2011
    ..Thus, cMyBP-C is a critical nodal point that has both important structural and signaling roles and whose modifications are known to cause significant human cardiac disease...
  16. pmc Altered myofilament stoichiometry in response to heart failure in a cardioprotective α-myosin heavy chain transgenic rabbit model
    Brian A Stanley
    Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA
    Proteomics Clin Appl 5:147-58. 2011
    ..Hypothesizing that MHC isoform content alterations would impact sarcomere and mitochondrial energetics protein complement, we investigated the impact of α-MHC overexpression on global cardiac protein expression...
  17. pmc A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function
    Sakthivel Sadayappan
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, IL, USA
    Circ Res 109:141-50. 2011
    ..In vitro and in vivo experiments suggest the nonequivalence of these sites and the potential importance of Ser-282 phosphorylation in modulating the protein's overall phosphorylation and myocardial function...
  18. pmc Electron microscopy and 3D reconstruction of F-actin decorated with cardiac myosin-binding protein C (cMyBP-C)
    Ji Young Mun
    Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
    J Mol Biol 410:214-25. 2011
    ..The location of binding was such that it could modulate tropomyosin position and would interfere with myosin head binding to actin...
  19. pmc Desmin-related cardiomyopathy: an unfolding story
    Patrick M McLendon
    Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Am J Physiol Heart Circ Physiol 301:H1220-8. 2011
    ....
  20. pmc Direct visualization of myosin-binding protein C bridging myosin and actin filaments in intact muscle
    Pradeep K Luther
    Molecular Medicine Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
    Proc Natl Acad Sci U S A 108:11423-8. 2011
    ..This binding implies a physical mechanism for communicating the relative sliding between thick and thin filaments that does not involve myosin and which could modulate the contractile process...
  21. pmc Quantum dot labeling strategies to characterize single-molecular motors
    Shane R Nelson
    Department of Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, VT, USA
    Methods Mol Biol 778:111-21. 2011
    ..High-resolution video microscopy and single-particle tracking of a Qdot-labeled MyoVa motor molecule allow the detection of individual steps in vitro and in live cells...
  22. pmc Measuring myosin cross-bridge attachment time in activated muscle fibers using stochastic vs. sinusoidal length perturbation analysis
    Bertrand C W Tanner
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA
    J Appl Physiol (1985) 110:1101-8. 2011
    ..This study demonstrates that white noise analysis can detect underlying molecular processes associated with dynamic muscle contraction comparable to sinusoidal analysis, but in a fraction of the time...
  23. pmc Myosin Va and myosin VI coordinate their steps while engaged in an in vitro tug of war during cargo transport
    M Yusuf Ali
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Proc Natl Acad Sci U S A 108:E535-41. 2011
    ..This model system emphasizes the physical communication between opposing motors bound to a common cargo and highlights the potential for modulating this interaction by changes in the cell's ionic milieu...
  24. pmc Isolation, electron microscopy and 3D reconstruction of invertebrate muscle myofilaments
    Roger Craig
    Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
    Methods 56:33-43. 2012
    ..It also highlights some of the key insights into filament function that have come from these studies...
  25. pmc Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials
    David A Kass
    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Ross Building, Room 858, 720 Rutland Avenue, Baltimore, MD 21205, USA
    Curr Heart Fail Rep 9:192-9. 2012
    ..This review discusses recent developments in the field, highlighting basic science and clinical studies...
  26. pmc Functional dissection of myosin binding protein C phosphorylation
    Manish K Gupta
    The Heart Institute, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    J Mol Cell Cardiol 64:39-50. 2013
    ..The new DAA and AAD constructs show that phosphorylation at one site in the absence of the ability to phosphorylate the other sites, depending upon the particular residues involved, can lead to severe cardiac remodeling and dysfunction. ..
  27. pmc Different head environments in tarantula thick filaments support a cooperative activation process
    Guidenn Sulbarán
    Centro de Biología Estructural, Instituto Venezolano de Investigaciones Cientificas IVIC, Caracas, Venezuela Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts
    Biophys J 105:2114-22. 2013
    ..In the interacting-head motif of relaxed filaments, only the free head RLCs are exposed, suggesting that the constitutive pSer-35 is on the free heads, consistent with the proposed mechanism...
  28. pmc Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction
    Peter P Rainer
    From the Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD P P R, S H, D i L, N K, D A K Division of Cardiology, Medical University of Graz, Austria P P R Department of Pediatrics, Cincinnati Children s Hospital, University of Cincinnati, Cincinnati, OH D V, J D M Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, OH J D M and Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan N K
    Circ Res 114:1246-57. 2014
    ..Broad inhibition of TGFβ early postinfarction has worsened post-myocardial infarction remodeling; however, this signaling displays potent cell specificity, and targeted suppression particularly in the myocyte could be beneficial...
  29. pmc Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
    Kinya Seo
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205
    Proc Natl Acad Sci U S A 111:1551-6. 2014
    ..Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management. ..
  30. pmc Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism
    Ji Young Mun
    Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655
    Proc Natl Acad Sci U S A 111:2170-5. 2014
    ..These results suggest that cMyBP-C may both modulate thin filament activity, by physically displacing tropomyosin from its low Ca(2+) position on actin, and govern contractile speed by an independent molecular mechanism. ..
  31. pmc Random myosin loss along thick-filaments increases myosin attachment time and the proportion of bound myosin heads to mitigate force decline in skeletal muscle
    Bertrand C W Tanner
    Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164, United States Electronic address
    Arch Biochem Biophys 552:117-27. 2014
    ..These simulations also illustrate that the pattern of myosin loss along thick-filaments influences ensemble cross-bridge behavior and maintenance of force throughout the sarcomere. ..
  32. pmc Three-dimensional organization of troponin on cardiac muscle thin filaments in the relaxed state
    Shixin Yang
    Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts
    Biophys J 106:855-64. 2014
    ..We now show how troponin, the Ca(2+) sensor, may control these movements, ultimately determining whether muscle contracts or relaxes. ..
  33. pmc Molecular modulation of actomyosin function by cardiac myosin-binding protein C
    Michael J Previs
    Department of Molecular Physiology and Biophysics, University of Vermont, 149 Beaumont Ave, HSRF Building Rm 116, Burlington, VT, 05405, USA
    Pflugers Arch 466:439-44. 2014
    ..Literature pertaining to how MyBP-C binding to the myosin motor domain and or actin leads to MyBP-C's dual modulatory roles that can impact actomyosin interactions are discussed. ..
  34. pmc Structure, sarcomeric organization, and thin filament binding of cardiac myosin-binding protein-C
    Roger Craig
    Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA
    Pflugers Arch 466:425-31. 2014
    ..We also discuss the effects that phosphorylation of cMyBP-C has on some of these structural features and how this might relate to cMyBP-C function in the beating heart. ..
  35. pmc Post-translational control of cardiac hemodynamics through myosin binding protein C
    Manish K Gupta
    The Heart Institute, Department of Pediatrics, The Cincinnati Children s Hospital Medical Center, Cincinnati, OH, 45229, USA
    Pflugers Arch 466:231-6. 2014
    ..Phosphorylation of the M domain can regulate the manner in which actin and myosin interact, affecting the cross bridge cycle and ultimately, cardiac hemodynamics. ..
  36. pmc Proteotoxicity: an underappreciated pathology in cardiac disease
    Marco Sandri
    Venetian Institute of Molecular Medicine VIMM, Padova, Italy Consiglio Nazionale delle Ricerche CNR Institute of Neuroscience, Padova, Italy Department of Biomedical Sciences, University of Padova, Padova, Italy
    J Mol Cell Cardiol 71:3-10. 2014
    ..This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy." ..
  37. pmc Proteasomal and lysosomal protein degradation and heart disease
    Xuejun Wang
    Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA Electronic address
    J Mol Cell Cardiol 71:16-24. 2014
    ..This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy". ..
  38. pmc Molecular mechanics of cardiac myosin-binding protein C in native thick filaments
    M J Previs
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Science 337:1215-8. 2012
    ..These results provide molecular insight into why cMyBP-C should be considered a member of a tripartite complex with actin and myosin that allows fine tuning of cardiac muscle contraction...
  39. pmc Cardiac myosin isoforms exhibit differential rates of MgADP release and MgATP binding detected by myocardial viscoelasticity
    Yuan Wang
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    J Mol Cell Cardiol 54:1-8. 2013
    ....
  40. pmc Phosphorylation modulates the mechanical stability of the cardiac myosin-binding protein C motif
    Arthur J Michalek
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA
    Biophys J 104:442-52. 2013
    ..These biophysical data provide both a mechanical and structural basis for cMyBP-C regulation by motif phosphorylation...
  41. pmc Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy
    Bradley M Palmer
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    J Mol Cell Cardiol 57:23-31. 2013
    ..9s(-1) in F764L/+, 32.9±4.5s(-1) in S532P/+ and 18.2±1.7s(-1) in +/+). These results suggest that elevated rates of force development and MgATP binding are features of cardiac myofilament function that underlie the development of DCM...
  42. pmc Structural basis of the relaxed state of a Ca2+-regulated myosin filament and its evolutionary implications
    John L Woodhead
    Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Proc Natl Acad Sci U S A 110:8561-6. 2013
    ..The reconstruction provides a native structural context for understanding past biochemical and biophysical studies of this model Ca(2+)-regulated myosin...
  43. pmc An endogenously produced fragment of cardiac myosin-binding protein C is pathogenic and can lead to heart failure
    Md Abdur Razzaque
    Department of Pediatrics, The Heart Institute, The Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Circ Res 113:553-61. 2013
    ..Elevated levels of the fragment can be detected in the diseased mouse and human heart, but its ability to interfere with normal cardiac function in the intact animal is unexplored...
  44. pmc An inverse power-law distribution of molecular bond lifetimes predicts fractional derivative viscoelasticity in biological tissue
    Bradley M Palmer
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT, USA
    Biophys J 104:2540-52. 2013
    ....
  45. pmc The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice
    Huabo Su
    Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD
    Circ Heart Fail 6:1049-57. 2013
    ..However, the physiological significance of CSN in a post-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts...
  46. pmc Cardiac myosin binding protein-C plays no regulatory role in skeletal muscle structure and function
    Brian Lin
    Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, USA
    PLoS ONE 8:e69671. 2013
    ....
  47. pmc Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation
    Kinya Seo
    From the Division of Cardiology, Department of Medicine K S, P P R, D i L, S H, D B, O H C, D A K and Department of Biomedical Engineering D A K, The Johns Hopkins Medical Institutions, Baltimore, MD Division of Cardiology, Medical University of Graz, Graz, Austria P P R and National Institute of Environmental Health Science, Research Triangle Park, NC L B
    Circ Res 114:823-32. 2014
    ..The relevant mechanotransducers and therapies to target them remain unclear...
  48. pmc A strain-dependency of Myosin off-rate must be sensitive to frequency to predict the B-process of sinusoidal analysis
    Bradley M Palmer
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Adv Exp Med Biol 682:57-75. 2010
    ....
  49. ncbi Tetrahydrobiopterin and cardiovascular disease
    An L Moens
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA
    Arterioscler Thromb Vasc Biol 26:2439-44. 2006
    ..This review discusses the biochemistry, physiology, and evolving therapeutic potential of BH4 for cardiovascular disease...
  50. pmc Effect of low pH on single skeletal muscle myosin mechanics and kinetics
    E P Debold
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Am J Physiol Cell Physiol 295:C173-9. 2008
    ....
  51. pmc Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay
    Walid Saber
    Department of Medicine, University of Vermont, College of Medicine, Burlington, VT 05405, USA
    J Mol Cell Cardiol 44:1053-61. 2008
    ....
  52. pmc High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury
    An L Moens
    Johns Hopkins Medical Institutions, Division of Cardiology, Baltimore, MD 21205, USA
    Circulation 117:1810-9. 2008
    ..Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury...
  53. pmc Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats
    Pal Pacher
    Section on Oxidative Stress Tissue Injury, Laboratories of Physiological Studies, National Institutes of Health NIAAA, 5625 Fishers Lane, MSC 9413, Bethesda, Maryland 20892 9413, USA
    Nat Protoc 3:1422-34. 2008
    ..The completion of the protocol takes 1-4 h (depending on the experimental design/end points)...
  54. ncbi Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil
    Takahiro Nagayama
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    J Pharmacol Exp Ther 326:380-7. 2008
    ..This may prove beneficial for enhancing the efficacy of PDE5 inhibitors in conditions with chronically reduced NOS activity...
  55. pmc Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome
    Maike Krenz
    Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Proc Natl Acad Sci U S A 105:18930-5. 2008
    ..The data demonstrate both necessity and sufficiency of increased ERK activation downstream of Shp2 in mediating abnormal valve development in a NS mouse model...
  56. pmc Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy
    An L Moens
    Johns Hopkins Medical Institutions, Division of Cardiology, Baltimore, MD 21205, USA
    Circulation 117:2626-36. 2008
    ..Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction...
  57. ncbi Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex
    Bradley M Palmer
    Dept of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Am J Physiol Heart Circ Physiol 294:H1939-47. 2008
    ..The sex-dependent development of HCM due to the R403Q myosin may then be inhibited by female sex hormones, which may additionally underlie the observed sex differences for pCa(50) and unloaded shortening velocity...
  58. pmc Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure
    J Scott Pattison
    Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Circulation 117:2743-51. 2008
    ....
  59. pmc Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes
    Manling Zhang
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    Cell Signal 20:2231-6. 2008
    ..These data confirm PDE5 expression, activity, and targeted inhibition by sildenafil in cardiomyocytes, as well as the role of this PDE in cardiomyocyte hypertrophy modulation...
  60. ncbi Heart failure-associated alterations in troponin I phosphorylation impair ventricular relaxation-afterload and force-frequency responses and systolic function
    Kenneth C Bilchick
    Dept of Pediatrics, Johns Hopkins Univ School of Medicine, 720 Rutland Ave, Ross Bldg 1144, Baltimore, MD 21205, USA
    Am J Physiol Heart Circ Physiol 292:H318-25. 2007
    ..Abnormal TnI phosphorylation observed in cardiac failure may explain exacerbated relaxation delay in response to increased afterload and contribute to blunted chronotropic reserve...
  61. ncbi Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation
    Takahiro Nagayama
    Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    Circulation 116:2399-408. 2007
    ..We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function...
  62. pmc Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling
    Carlo G Tocchetti
    Cardiology Division, Johns Hopkins Medical Institutions, 720 Rutland Ave, Baltimore, MD 21205, USA
    Circ Res 100:96-104. 2007
    ..Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca(2+) cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure...
  63. ncbi Functional consequences of a mutation in an expressed human alpha-cardiac actin at a site implicated in familial hypertrophic cardiomyopathy
    Carol S Bookwalter
    Department of Molecular Physiology, University of Vermont, Burlington, VT 05405, USA
    J Biol Chem 281:16777-84. 2006
    ....
  64. ncbi Differential regional gene expression from cardiac dyssynchrony induced by chronic right ventricular free wall pacing in the mouse
    Kenneth C Bilchick
    Division of Cardiology, Department of Medicine, School of Medicine, Baltimore, Maryland, USA
    Physiol Genomics 26:109-15. 2006
    ..Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart...
  65. ncbi Role of oxidative stress in cardiac hypertrophy and remodeling
    Eiki Takimoto
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    Hypertension 49:241-8. 2007
  66. ncbi Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface
    Timothy A McKinsey
    Gilead Colorado, Inc, 7575 West 103rd Avenue, Westminster, Colorado 80021, USA
    Nat Rev Drug Discov 6:617-35. 2007
    ....
  67. ncbi Therapeutic potential of tetrahydrobiopterin for treating vascular and cardiac disease
    An L Moens
    Department of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    J Cardiovasc Pharmacol 50:238-46. 2007
    ..This review summarizes these recent studies focusing on the biochemistry and pharmacology of BH4 and its potential role for treating cardiovascular disease...
  68. pmc Two-state model of acto-myosin attachment-detachment predicts C-process of sinusoidal analysis
    Bradley M Palmer
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA
    Biophys J 93:760-9. 2007
    ..Experimental results from activated cardiac muscle examined at different temperatures and containing predominately alpha- or beta-myosin heavy chain isoforms were found to be consistent with the above interpretation...
  69. pmc The R403Q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin interface
    Niels Volkmann
    Burnham Institute for Medical Research, La Jolla, California, United States of America
    PLoS ONE 2:e1123. 2007
    ..It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype...
  70. ncbi Distribution and structure-function relationship of myosin heavy chain isoforms in the adult mouse heart
    Maike Krenz
    Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    J Biol Chem 282:24057-64. 2007
    ....
  71. ncbi Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5
    Eiki Takimoto
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    Circulation 115:2159-67. 2007
    ..The potential role of differential cGMP and protein kinase G stimulation by these 2 modulators was also studied...
  72. pmc Mutation of a conserved glycine in the SH1-SH2 helix affects the load-dependent kinetics of myosin
    Neil M Kad
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405, USA
    Biophys J 92:1623-31. 2007
    ..These results imply that conformational changes near the conserved G709 are critical for the transmission of mechanochemical information between myosin's active site and lever arm...
  73. pmc Cargo transport: molecular motors navigate a complex cytoskeleton
    Jennifer L Ross
    University of Massachusetts, Department of Physics, Amherst, MA 01003, USA
    Curr Opin Cell Biol 20:41-7. 2008
    ....
  74. pmc Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone
    Susan Lowey
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    J Biol Chem 283:20579-89. 2008
    ..Thus, the functional consequences of the mutation are fundamentally changed depending upon the context of the cardiac MHC isoform...
  75. pmc Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload
    Takahiro Nagayama
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    J Am Coll Cardiol 53:207-15. 2009
    ..This study sought to test the efficacy of phosphodiesterase type 5A (PDE5A) inhibition for treating advanced hypertrophy/remodeling caused by pressure overload, and to elucidate cellular and molecular mechanisms for this response...
  76. pmc Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models
    Norimichi Koitabashi
    Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
    Circ Res 105:12-5. 2009
    ..Careful attention to controls, reduced tamoxifen dosing and/or use of raloxifene is advised with this model...
  77. pmc Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway
    Steven Hsu
    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building, Room 850, Baltimore, MD 21205, USA
    Cardiovasc Res 81:301-9. 2009
    ..We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL...
  78. pmc Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background
    Sakthivel Sadayappan
    Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Ohio, USA
    Circulation 119:1253-62. 2009
    ..We determined the effect(s) of cMyBP-C phosphorylation in a beta-MyHC transgenic mouse heart in which >80% of the alpha-MyHC was replaced by beta-MyHC, which is the predominant myosin isoform in human cardiac muscle...
  79. pmc Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor
    An L Moens
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    J Mol Cell Cardiol 47:576-85. 2009
    ..These data suggest a cardioprotective role for the beta3-AR in modulating oxidative stress and adverse remodeling in the failing heart...
  80. pmc Effects of myosin heavy chain manipulation in experimental heart failure
    Jeanne James
    The Heart Institute, Cincinnati Children s Hospital Medical Center and the University of Cincinnati School of Medicine, 241 Albert Sabin Way MLC 7020, Cincinnati, OH 45229 3039, USA
    J Mol Cell Cardiol 48:999-1006. 2010
    ..Future considerations of myosin isoform manipulation as a therapeutic strategy should consider the underlying etiology of cardiac dysfunction...
  81. pmc Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5
    Manling Zhang
    Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    J Am Coll Cardiol 56:2021-30. 2010
    ....
  82. pmc PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation
    Dong I Lee
    Ross 858, Division of Cardiology, Department of Medicine, Johns Hopkins University Medical Institutions, Baltimore, MD, 21205, USA
    Basic Res Cardiol 105:337-47. 2010
    ..These data support a cascade involving beta3-AR stimulation, and subsequent PKG-dependent TnI S23, S24 phosphorylation as primary factors underlying the capacity of acute PDE5A inhibition to blunt myocardial beta-adrenergic stimulation...
  83. pmc Manipulation of death pathways in desmin-related cardiomyopathy
    Alina Maloyan
    Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children s Hospital, Cincinnati, Ohio, USA
    Circ Res 106:1524-32. 2010
    ..However, the role of mitochondrial dysfunction and apoptosis in the overall course of the disease was unclear...
  84. pmc Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro
    Edward P Debold
    Department of Molecular Physiology and Biophysics, University of Vermont, College of Medicine, 149 Beaumont Drive, Burlington, VT 05405, USA
    J Mol Cell Cardiol 48:286-92. 2010
    ..In conclusion, E99K inhibits the activation of the thin filament by myosin strong-binding whereas R312H demonstrates enhanced calcium activation...
  85. pmc Effects of cardiac myosin isoform variation on myofilament function and crossbridge kinetics in transgenic rabbits
    Takeki Suzuki
    Department of Medicine, Cardiology Unit, Fletcher Allen Health Care, Burlington, VT 05401, USA
    Circ Heart Fail 2:334-41. 2009
    ..This study was undertaken to identify a myofilament-based mechanism underlying tachycardia-induced cardiomyopathy protection and to extrapolate the impact of MHC isoform variation on myofilament function in human hearts...
  86. pmc Cardiac myosin binding protein-C is essential for thick-filament stability and flexural rigidity
    Lori R Nyland
    Department of Biology, University of Vermont, Burlington, Vermont 05405, USA
    Biophys J 96:3273-80. 2009
    ..These results provide what we consider a new understanding for the critical role of cMyBP-C in defining normal cardiac output by sustaining force and muscle stiffness...
  87. pmc Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice
    Eiki Takimoto
    Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Clin Invest 119:408-20. 2009
    ..Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors...
  88. pmc Functional effects of nemaline myopathy mutations on human skeletal alpha-actin
    Becky M Miller
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405, USA
    J Biol Chem 283:19379-88. 2008
    ..If these subtle changes in polymerization observed in vitro are amplified in the context of the sarcomere, it could in principle be one of the primary insults that triggers the development of nemaline myopathy...
  89. pmc Load and Pi control flux through the branched kinetic cycle of myosin V
    Neil M Kad
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405, USA
    J Biol Chem 283:17477-84. 2008
    ..Our model includes P(i) release prior to the most load-dependent step in the cycle, implying that P(i) release and load both act as checkpoints that control the flux through two parallel pathways...
  90. pmc Myosin V and Kinesin act as tethers to enhance each others' processivity
    M Yusuf Ali
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405
    Proc Natl Acad Sci U S A 105:4691-6. 2008
    ..The resulting run length enhancement likely contributes to the successful delivery of cargo in the cell...
  91. pmc Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations
    Tomoki Nakamura
    Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229 3039, USA
    Proc Natl Acad Sci U S A 106:15436-41. 2009
    ....
  92. pmc Biochemical and mechanical dysfunction in a mouse model of desmin-related myopathy
    Alina Maloyan
    Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Ohio 45229 3039, USA
    Circ Res 104:1021-8. 2009
    ..Our findings indicate that oxypurinol treatment largely prevented mitochondrial deficiency in DRM but that contractility was not improved because of mechanical deficits in passive cytoskeletal stiffness...
  93. pmc Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development
    Tomoki Nakamura
    Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Proc Natl Acad Sci U S A 106:11270-5. 2009
    ....
  94. ncbi Regulation of nerve growth factor in the heart: the role of the calcineurin-NFAT pathway
    Obaida R Rana
    Department of Cardiology, Angiology and Pulmonology, Medical Faculty, RWTH Aachen University, Pauwelsstr 30, D 52074 Aachen, Germany
    J Mol Cell Cardiol 46:568-78. 2009
    ..Nevertheless, the calcineurin-NFAT pathway may provide promising starting points for new pharmacological strategies to prevent SNS in the heart...
  95. pmc Random walk of processive, quantum dot-labeled myosin Va molecules within the actin cortex of COS-7 cells
    Shane R Nelson
    Department of Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, Vermont, USA
    Biophys J 97:509-18. 2009
    ..Monte Carlo modeling suggests that the random nature of the trajectories represents processive myoVa motors undergoing a random walk through the dense and randomly oriented cortical actin network...
  96. pmc Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition
    Takahiro Nagayama
    Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, MD 21287, USA
    J Mol Cell Cardiol 46:560-7. 2009
    ..Such regulation could impact responses of varying disease models to PDE5A inhibitors...
  97. pmc Diffusive movement of processive kinesin-1 on microtubules
    Hailong Lu
    Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA
    Traffic 10:1429-38. 2009
    ..This mechanism may facilitate the ability of kinesin to pick up cargo, and/or allow the kinesin/cargo complex to stay bound after encountering obstacles...
  98. pmc Collaborative dynamic DNA scanning by nucleotide excision repair proteins investigated by single- molecule imaging of quantum-dot-labeled proteins
    Neil M Kad
    Department of Biological Sciences, University of Essex, Colchester, Essex CO4 3SQ, UK
    Mol Cell 37:702-13. 2010
    ..Three types of sliding motion were characterized: random diffusion, paused motion, and directed motion. This UvrB-induced change in mode of searching permits more rapid and efficient scanning of the genome for damage...

Research Grants30

  1. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..