INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION

Summary

Principal Investigator: R John Solaro
Abstract: DESCRIPTION (provided by applicant): Our program project addresses the mechanisms of processes triggered by stresses on the heart that are adaptive and offset the stressor or are maladaptive and exacerbate the stressor leading to decompensation and heart failure. The theme of the program that ties the projects together is our hypothesis that alterations at the level of cardiac sarcomeres and costameres are primary and critical mechanisms in these processes and the transition from adaptation to maladaptatlon. The program has four highly interactive and synergistic projects approaching our hypothesis with perspectives and approaches that complement and reinforce each other. Administrative, Animal, and Proteomics/ Analytical Biochemistry Cores support these projects and coordinate their activities to ensure synergy and cohesion among these approaches. Objectives of Project 1 (Solaro) emphasize phospho-protein analysis and molecular mechanisms of altered sarcomeric protein function in response to metabolic signaling activation via AMPK/Paki (with emphasis on the evolution and rescue of familial hypertrophic cardiomyopathy (FHC);and via PKCe, and with emphasis on dilated cardiomyopathy, novel phosphorylation sites and on rescue. In Project 2 (Russell/Samarel) the overall objective is to test the hypothesis that mechanical strain regulates cell lengthening by phosphorylation of focal adhesion kinase at the costamere leading to actin capping by CapZ. In Project 3 (LewandoskI), the overall objective is to elucidate the potential for, and the extent to which myofilament modifications induce changes in metabolic phenotype and elucidate adaptive and/or cardioprotective shifts in metabolic pathways, In Project 4 (de Tombe) the major objective is to determine the structure-function relations of sarcomeric protein phosphorylation and myofilament function in the development of congestive heart failure (CHF) in a well-established model of CHF in the guinea-pig secondary to pressure- or volume overload. Approaches to these objectives include novel animal models, determination of cardiac hemodynamics and metabolism with NMR, mechanical studies at the level of the heart, myocytes, and myofibrils, proteomics, and molecular studies at the protein level. The approaches are directly related to the goal of translating findings in the projects to the diagnosis and to the development of novel therapies in familial and acquired cardiomyopathies and heart failure. Familial and acquired heart failure are among the most prevalent disorders of the heart and responsible for the majority of hospital admissions in the USA. Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract)
Funding Period: 2000-06-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain
    Sarah B Scruggs
    Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois 60612, USA
    Mol Cell Proteomics 9:1804-18. 2010
  2. pmc The significance of regulatory light chain phosphorylation in cardiac physiology
    Sarah B Scruggs
    University of California Los Angeles, Department of Physiology, Division of Cardiology, 90095, USA
    Arch Biochem Biophys 510:129-34. 2011
  3. pmc Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes
    J P Sarkey
    Department of Cell and Molecular Physiology, Loyola University Medical Center, Maywood, IL, USA
    J Mol Cell Cardiol 50:1044-55. 2011
  4. pmc Beneficial effects of SR33805 in failing myocardium
    Younss Ait Mou
    Inserm U1046, Universite Montpellier 1, Montpellier, France
    Cardiovasc Res 91:412-9. 2011
  5. pmc Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury
    Emmanuel Eroume A Egom
    Hull and York Medical School, Academic Cardiology, Kingston upon Hull, United Kingdom
    Am J Physiol Heart Circ Physiol 301:H1487-95. 2011
  6. pmc Expression of tropomyosin-κ induces dilated cardiomyopathy and depresses cardiac myofilament tension by mechanisms involving cross-bridge dependent activation and altered tropomyosin phosphorylation
    Chehade N Karam
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave M C 901, Chicago, IL 60612 7342, USA
    J Muscle Res Cell Motil 31:315-22. 2011
  7. pmc Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction
    Krystyna M Shioura
    Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, USA
    Am J Physiol Regul Integr Comp Physiol 300:R361-8. 2011
  8. pmc Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy
    Miensheng Chu
    Department of Physiology, Loyola University Medical Center, Maywood, IL, USA
    Cardiovasc Res 92:409-19. 2011
  9. pmc Equal force recovery in dysferlin-deficient and wild-type muscles following saponin exposure
    Piming Zhao
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
    J Biomed Biotechnol 2011:235216. 2011
  10. pmc Interventricular differences in myofilament function in experimental congestive heart failure
    Rashad J Belin
    Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA
    Pflugers Arch 462:795-809. 2011

Research Grants

Detail Information

Publications161 found, 100 shown here

  1. pmc A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain
    Sarah B Scruggs
    Department of Physiology and Biophysics, University of Illinois, Chicago, Illinois 60612, USA
    Mol Cell Proteomics 9:1804-18. 2010
    ....
  2. pmc The significance of regulatory light chain phosphorylation in cardiac physiology
    Sarah B Scruggs
    University of California Los Angeles, Department of Physiology, Division of Cardiology, 90095, USA
    Arch Biochem Biophys 510:129-34. 2011
    ..Data demonstrating altered levels of RLC phosphorylation in comparisons of samples from normal and stressed human hearts indicate the significance of these findings in translational medicine...
  3. pmc Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes
    J P Sarkey
    Department of Cell and Molecular Physiology, Loyola University Medical Center, Maywood, IL, USA
    J Mol Cell Cardiol 50:1044-55. 2011
    ..Together, these data demonstrate that knockdown of Nogo-A may serve as a novel therapeutic strategy to prevent the loss of cardiomyocytes following ischemic/hypoxic injury...
  4. pmc Beneficial effects of SR33805 in failing myocardium
    Younss Ait Mou
    Inserm U1046, Universite Montpellier 1, Montpellier, France
    Cardiovasc Res 91:412-9. 2011
    ..Therefore, the aim of the present study was to evaluate the effects of SR33805 on contractile properties in ischaemic failing hearts after myocardial infarction (MI) in vivo and in vitro at the cellular level...
  5. pmc Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury
    Emmanuel Eroume A Egom
    Hull and York Medical School, Academic Cardiology, Kingston upon Hull, United Kingdom
    Am J Physiol Heart Circ Physiol 301:H1487-95. 2011
    ..Further study on a mouse model of cardiac specific deletion of Pak1 demonstrates a crucial role of Pak1 in cardiac protection against ischemia/reperfusion injury...
  6. pmc Expression of tropomyosin-κ induces dilated cardiomyopathy and depresses cardiac myofilament tension by mechanisms involving cross-bridge dependent activation and altered tropomyosin phosphorylation
    Chehade N Karam
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave M C 901, Chicago, IL 60612 7342, USA
    J Muscle Res Cell Motil 31:315-22. 2011
    ..Our results identify a novel mode of myofilament desensitization to Ca(2+) associated with a DCM linked switch in TM isoform population...
  7. pmc Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction
    Krystyna M Shioura
    Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, USA
    Am J Physiol Regul Integr Comp Physiol 300:R361-8. 2011
    ....
  8. pmc Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy
    Miensheng Chu
    Department of Physiology, Loyola University Medical Center, Maywood, IL, USA
    Cardiovasc Res 92:409-19. 2011
    ....
  9. pmc Equal force recovery in dysferlin-deficient and wild-type muscles following saponin exposure
    Piming Zhao
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
    J Biomed Biotechnol 2011:235216. 2011
    ..Our data suggest that dysferlin is unlikely involved in repairing saponin-induced membrane damage and that the slow muscle is more efficient than the fast muscle in repairing such damage...
  10. pmc Interventricular differences in myofilament function in experimental congestive heart failure
    Rashad J Belin
    Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA
    Pflugers Arch 462:795-809. 2011
    ..Furthermore, myofilament dysfunction is greater in the LV compared to the RV due in part to increased PKC-α activation and phosphorylation of cTnI and cTnT...
  11. pmc New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I
    Marcus Henze
    Department of Physiology and Biophysics, University of Illinois, Chicago, IL 60612, USA
    Biochim Biophys Acta 1833:823-32. 2013
    ..This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction...
  12. pmc Protein kinase A changes calcium sensitivity but not crossbridge kinetics in human cardiac myofibrils
    John S Walker
    Division of Cardiology, Dept of Medicine, Univ of Colorado, Denver, Aurora CO 80045, USA
    Am J Physiol Heart Circ Physiol 301:H138-46. 2011
    ....
  13. pmc Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A
    Domenico M Taglieri
    Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, M C 901, Chicago, IL 60612 7342, USA
    J Mol Cell Cardiol 51:988-96. 2011
    ..Active Pak-1 is a natural inhibitor of Erk1/2 and a novel anti-hypertrophic signaling molecule upstream of PP2A...
  14. pmc Methods in cardiomyocyte isolation, culture, and gene transfer
    William E Louch
    Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, Oslo, Norway
    J Mol Cell Cardiol 51:288-98. 2011
    ..Gene transfer techniques for neonatal and adult cardiomyocytes are also reviewed, including methods for transfection (liposome, electroporation) and viral-based gene delivery...
  15. pmc Focal adhesion kinase-related nonkinase inhibits vascular smooth muscle cell invasion by focal adhesion targeting, tyrosine 168 phosphorylation, and competition for p130(Cas) binding
    Yevgeniya E Koshman
    Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
    Arterioscler Thromb Vasc Biol 31:2432-40. 2011
    ..FRNK inhibits both FAK and proline-rich tyrosine kinase 2 (PYK2) in cultured VSMCs, and both kinases may be involved in VSMC invasion during vascular remodeling...
  16. pmc The ShcA phosphotyrosine docking protein uses distinct mechanisms to regulate myocyte and global heart function
    Rachel D Vanderlaan
    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada
    Circ Res 108:184-93. 2011
    ..Therefore, ShcA could be a potential hub for downstream TK signaling in the myocardium...
  17. pmc Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia
    Kayla M Pound
    Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    J Mol Cell Cardiol 51:236-43. 2011
    ..This article is part of a Special Issue entitled "Possible Editorial"...
  18. pmc Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, α-tropomyosin D175N
    Robert D Gaffin
    Department of Physiology and Biophysics, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Am J Physiol Heart Circ Physiol 301:H1646-55. 2011
    ..However, chronic NIC had little effect on heart rate, LV pressure, -dP/dt, LV wall and chamber dimensions, or collagen content for either group of mice...
  19. pmc Ablation of iNOS delays cardiac contractile dysfunction in chronic hypertension
    Fernando A L Dias
    Department of Medicine, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, IL 60612, USA
    Front Biosci (Elite Ed) 2:312-24. 2010
    ..In conclusion, our data demonstrate that NO production via iNOS plays an important role in modulating cardiac function after moderate AoB that mimics long-term hypertension in humans...
  20. pmc Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity
    Ganapathy Jagatheesan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Albert B Sabin Way, Cincinnati, OH 45267 0524, USA
    J Muscle Res Cell Motil 31:227-39. 2010
    ..This is significant in relation to current ideas on the control mechanism of the steep relation between Ca(2+) and tension...
  21. pmc Novel bradykinin signaling in adult rat cardiac myocytes through activation of p21-activated kinase
    Yunbo Ke
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, USA
    Am J Physiol Heart Circ Physiol 298:H1283-9. 2010
    ..Our studies indicate a novel signaling mechanism for BK in adult rat cardiac myocytes and support our hypothesis that Pak 1 is a significant regulator of phosphatase activity in the heart...
  22. pmc Migration and proliferation of human mesenchymal stem cells is stimulated by different regions of the mechano-growth factor prohormone
    John M Collins
    Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60612 7342, USA
    J Mol Cell Cardiol 49:1042-5. 2010
    ..It seems possible that regions of the IGF prohormone may act differentially, or in a combinatorial manner, to benefit cardiac tissue recovery after injury...
  23. pmc Signaling responses after exposure to 5 alpha-dihydrotestosterone or 17 beta-estradiol in norepinephrine-induced hypertrophy of neonatal rat ventricular myocytes
    Yevgeniya E Koshman
    Department of Physiology and Biophysics, University of Illinois at Chicago, MC 901, 835 South Wolcott Ave, Chicago, IL 60612 7342, USA
    J Appl Physiol (1985) 108:686-96. 2010
    ..This is the first report of rapid, nongenomic sex hormone signaling via FAK activation and altered FAK trafficking to the nucleus in heart cells...
  24. 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...
  25. pmc Cardioprotection in ischemia/reperfusion injury: spotlight on sphingosine-1-phosphate and bradykinin signalling
    Emmanuel Eroume A Egom
    Victoria Hospital, Cardiology, Hayfield Road, Kirkcaldy, Fife KY2 5AH, UK
    Prog Biophys Mol Biol 103:142-7. 2010
    ....
  26. pmc Phosphorylation of cardiac troponin I at protein kinase C site threonine 144 depresses cooperative activation of thin filaments
    Qun Wei Lu
    Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Biol Chem 285:11810-7. 2010
    ..These data highlight the importance of thin filament-based cooperative mechanisms in cardiac regulation, with implications for mechanisms of control of function in normal and pathological hearts...
  27. pmc Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform
    Sudarsan Rajan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267 0524, USA
    Circulation 121:410-8. 2010
    ..Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear...
  28. pmc FTY720 prevents ischemia/reperfusion injury-associated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling
    E Eroume A Egom
    Cardiovascular Research Group, School of Clinical and Laboratory Sciences, The University of Manchester, Manchester M13 9NT, UK
    J Mol Cell Cardiol 48:406-14. 2010
    ..Our data also indicate, for the first time, that the cardioprotective effect of FTY720 is likely to involve activation of signaling through the Pak1...
  29. pmc H2O2 alters rat cardiac sarcomere function and protein phosphorylation through redox signaling
    Benjamin S Avner
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612 7342, USA
    Am J Physiol Heart Circ Physiol 299:H723-30. 2010
    ..These data provide evidence that PKC-dependent redox signaling affects the function of cardiac myofilaments and indicate modification of specific proteins through this signaling mechanism...
  30. pmc Removal of the cardiac troponin I N-terminal extension improves cardiac function in aged mice
    Brandon J Biesiadecki
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 285:19688-98. 2010
    ....
  31. pmc Sarcomere control mechanisms and the dynamics of the cardiac cycle
    R John Solaro
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612, USA
    J Biomed Biotechnol 2010:105648. 2010
    ..Application of these ideas to translational medicine and rationale drug design forms an important rationale for detailed understanding of these processes...
  32. pmc Delayed enrichment of mesenchymal cells promotes cardiac lineage and calcium transient development
    Liliana Grajales
    Department of Physiology and Biophysics, Section of Cardiology and the Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Mol Cell Cardiol 48:735-45. 2010
    ..Enrichment with CD117/Sca-1 to establish lineage commitment followed by DHPR-alpha2 in lineage developing cells may enhance the therapeutic potential of these cells for transplantation...
  33. pmc Hypertrophy, gene expression, and beating of neonatal cardiac myocytes are affected by microdomain heterogeneity in 3D
    Matthew W Curtis
    Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
    Biomed Microdevices 12:1073-85. 2010
    ..This approach of defining physical cues as independent features may help to advance the elemental design considerations for scaffolds in cardiac tissue engineering and therapeutic microdevices...
  34. pmc Myofilament length dependent activation
    Pieter P de Tombe
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Chicago, IL 60153, USA
    J Mol Cell Cardiol 48:851-8. 2010
    ....
  35. pmc Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity
    Joshua D Lovelock
    Section of Cardiology, University of Illinois at Chicago, 60612, USA
    Circ Res 110:841-50. 2012
    ..Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux...
  36. pmc Myofilament Length-Dependent Activation Develops within 5 ms in Guinea-Pig Myocardium
    Ryan D Mateja
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Medical Center, Maywood, Illinois and Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois
    Biophys J 103:L13-5. 2012
    ..We conclude that the transduction of the length signal by the cardiac sarcomere to modulate thin filament activation levels occurs virtually instantaneously, possibly resulting from structural rearrangements of the contractile proteins...
  37. pmc Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy
    Emily M Schulz
    From the Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
    J Biol Chem 288:28925-35. 2013
    ..This is the first study to demonstrate that decreasing phosphorylation of tropomyosin can rescue a hypertrophic cardiomyopathic phenotype. ..
  38. pmc Phosphatidylinositol 4,5-bisphosphate regulates CapZβ1 and actin dynamics in response to mechanical strain
    Jieli Li
    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
    Am J Physiol Heart Circ Physiol 305:H1614-23. 2013
    ..This suggests that after many hours of cyclic strain, a possible mechanism for cell hypertrophy is the accumulation of thin filament assembly triggered partially by the increased PIP2 level and its binding to CapZ...
  39. pmc Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation
    Christopher A Koczor
    Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
    Physiol Genomics 45:590-6. 2013
    ..Epigenetic and genetic changes result in changes in mtDNA and in nucleotide substrates for mtDNA replication and underpin energy starvation in DCM...
  40. pmc Detection of differentially methylated gene promoters in failing and nonfailing human left ventricle myocardium using computation analysis
    Christopher A Koczor
    Department of Pathology, Emory University, Atlanta, Georgia, USA
    Physiol Genomics 45:597-605. 2013
    ..This study documents that rigorous computational analysis applied to microarray analysis of healthy and diseased human heart samples helps to define clinically relevant DNA methylation and expressional changes in DCM. ..
  41. pmc Regulation of connective tissue growth factor gene expression and fibrosis in human heart failure
    Yevgeniya E Koshman
    Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
    J Card Fail 19:283-94. 2013
    ..Connective tissue growth factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited...
  42. pmc The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium
    Michelle M Monasky
    Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois and
    Am J Physiol Heart Circ Physiol 305:H856-66. 2013
    ..Selective activation of β-arrestin-dependent pathways may provide advantages over conventional AT1R blockers. ..
  43. pmc Mechanisms of Ca²+ handling in zebrafish ventricular myocytes
    Elisa Bovo
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL, 60153, USA
    Pflugers Arch 465:1775-84. 2013
    ..This difference is due to a low sensitivity of RyRs to cytosolic [Ca(2+)]...
  44. pmc Structural basis for the in situ Ca(2+) sensitization of cardiac troponin C by positive feedback from force-generating myosin cross-bridges
    Daniel C Rieck
    Gene and Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164, USA
    Arch Biochem Biophys 537:198-209. 2013
    ....
  45. pmc Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy
    Yevgeniya E Koshman
    Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA
    J Mol Cell Cardiol 72:281-91. 2014
    ..5±1.0ms), and reduced LV remodeling (LVRI=4.9±0.1). Cardiomyocyte-specific expression of CRNK improves contractile function and slows LV remodeling in a mouse model of DCM. ..
  46. pmc Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium
    Namthip Witayavanitkul
    From the Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, Illinois 60153
    J Biol Chem 289:8818-27. 2014
    ....
  47. pmc Cardiac myosin binding protein-C as a central target of cardiac sarcomere signaling: a special mini review series
    Sakthivel Sadayappan
    Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL, 60153 5500, USA
    Pflugers Arch 466:195-200. 2014
    ..Starting from this issue, Pflügers Archiv European Journal of Physiology will publish two invited mini review articles each month to discuss the most recent advances in the study of cMyBP-C. ..
  48. pmc Focal adhesion signaling in heart failure
    Allen M Samarel
    The Cardiovascular Institute and the Department of Medicine, Loyola University Chicago Stritch School of Medicine, Building 110, Rm 5222, 2160 South First Avenue, Maywood, IL, 60153, USA
    Pflugers Arch 466:1101-11. 2014
    ..Finally, some speculations and directions for future study are provided for this rapidly developing field of research. ..
  49. pmc Characterization and validation of new tools for measuring site-specific cardiac troponin I phosphorylation
    Stephen F Thoemmes
    University of Colorado Denver, Dept of Medicine Cardiology, Aurora, CO 80045, United States
    J Immunol Methods 403:66-71. 2014
    ..These new tools should allow a more accurate assessment and a better understanding of the role of TnI phosphorylation in the response of the heart to pathologic stress...
  50. pmc Novel approaches to determine contractile function of the isolated adult zebrafish ventricular cardiac myocyte
    Alexey V Dvornikov
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
    J Physiol 592:1949-56. 2014
    ..We conclude that the zebrafish is a valid model system for the study of cardiac contractile structure-function relationships. ..
  51. pmc Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy
    David Barefield
    Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, Illinois
    Am J Physiol Heart Circ Physiol 306:H807-15. 2014
    ..43) and E'/A' (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM. ..
  52. pmc The role of dyadic organization in regulation of sarcoplasmic reticulum Ca(2+) handling during rest in rabbit ventricular myocytes
    Elisa Bovo
    Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois
    Biophys J 106:1902-9. 2014
    ..Such control of the dyadic [Ca(2+)] by NCX play a critical role in suppressing Ca(2+) sparks during rest. ..
  53. pmc A novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T-cells) signaling and periostin
    Wei Liu
    University of Manchester, Manchester, United Kingdom
    Circ Heart Fail 6:833-44. 2013
    ..Growing evidence indicates that restraining hypertrophy could be beneficial; here, we discovered that FTY-720, an immunomodulator for treating multiple sclerosis, can reverse existing cardiac hypertrophy/fibrosis...
  54. pmc Overexpression of inducible 70-kDa heat shock protein in mouse improves structural and functional recovery of skeletal muscles from atrophy
    Elen H Miyabara
    Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Lineu Prestes Av 2415, Sao Paulo, Sao Paulo, 05508 000, Brazil
    Pflugers Arch 463:733-41. 2012
    ..These results suggest that HSP70 improves structural and functional recovery of skeletal muscle after disuse atrophy, and this effect might be associated with preservation of satellite cell amount...
  55. pmc Impact of titin isoform on length dependent activation and cross-bridge cycling kinetics in rat skeletal muscle
    Ryan D Mateja
    Department of Cell and Molecular Physiology, Loyola University Medical Center, Maywood, IL 60153, USA
    Biochim Biophys Acta 1833:804-11. 2013
    ..This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction...
  56. pmc Pathogenic properties of the N-terminal region of cardiac myosin binding protein-C in vitro
    Suresh Govindan
    Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
    J Muscle Res Cell Motil 33:17-30. 2012
    ..By elucidating the deleterious effects of endogenously expressed cMyBP-C N-terminal fragments on sarcomere function, these data contribute to the understanding of contractile dysfunction following myocardial injury...
  57. pmc Phosphoprotein abundance changes in hypertensive cardiac remodeling
    Kumar Kotlo
    Department of Medicine, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA
    J Proteomics 77:1-13. 2012
    ..The results include previously described and novel phosphoproteins in cardiac hypertrophy and systolic failure...
  58. pmc p21-activated kinase improves cardiac contractility during ischemia-reperfusion concomitant with changes in troponin-T and myosin light chain 2 phosphorylation
    Michelle M Monasky
    Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 60612 7342, USA
    Am J Physiol Heart Circ Physiol 302:H224-30. 2012
    ..Thus, results of our study provide a basis for targeting a novel pathway, including Pak1, in the therapies for patients with ischemic events...
  59. pmc Maintenance of adult cardiac function requires the chromatin factor Asxl2
    Hsiao Lei Lai
    Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA
    J Mol Cell Cardiol 53:734-41. 2012
    ....
  60. pmc Myocardial infarction in mice alters sarcomeric function via post-translational protein modification
    Benjamin S Avner
    Department of Physiology and Biophysics, M C 901, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612 7342, USA
    Mol Cell Biochem 363:203-15. 2012
    ..Our data indicate important structural and functional alterations to the cardiac sarcomere after MI, and the contribution of protein oxidation to this process...
  61. pmc AMP-activated protein kinase phosphorylates cardiac troponin I at Ser-150 to increase myofilament calcium sensitivity and blunt PKA-dependent function
    Benjamin R Nixon
    Department of Physiology and Cell Biology and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
    J Biol Chem 287:19136-47. 2012
    ....
  62. pmc Post-translational modifications of myofilament proteins involved in length-dependent prolongation of relaxation in rabbit right ventricular myocardium
    Michelle M Monasky
    Department of Physiology and Cell Biology, College of Medicine and D Davis Heart Lung Institute, The Ohio State University, 1645 Neil Avenue, Columbus, OH 43210 1218, USA
    Arch Biochem Biophys 535:22-9. 2013
    ..Our data provide evidence for two signaling kinases acting upon myofilament proteins during length-dependent activation, and provide further insight for length-dependent myofilament function...
  63. pmc Microdomain heterogeneity in 3D affects the mechanics of neonatal cardiac myocyte contraction
    Matthew W Curtis
    Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
    Biomech Model Mechanobiol 12:95-109. 2013
    ....
  64. pmc Conserved Asp-137 is important for both structure and regulatory functions of cardiac α-tropomyosin (α-TM) in a novel transgenic mouse model expressing α-TM-D137L
    Sumeyye Yar
    Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 288:16235-46. 2013
    ..Thus, our results provide insight into the link between flexibility of TM and its function in ejecting hearts...
  65. pmc Contractile protein phosphorylation predicts human heart disease phenotypes
    Lori A Walker
    Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
    Am J Physiol Heart Circ Physiol 304:H1644-50. 2013
    ..Defining these changes in progressive heart disease may provide important diagnostic and treatment information...
  66. pmc CapZ and actin capping dynamics increase in myocytes after a bout of exercise and abates in hours after stimulation ends
    Ying Hsi Lin
    Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612, USA
    J Appl Physiol (1985) 114:1603-9. 2013
    ..This adaptive mechanism, which is probably regulating thin-filament addition, declines a few hours after the end of a bout of exercise...
  67. pmc The right ventricle: biologic insights and response to disease: updated
    Lori A Walker
    University of Colorado Denver, CO, USA
    Curr Cardiol Rev 9:73-81. 2013
    ..The updated version of this review now acknowledges recent advances in the understanding of metabolic, inflammatory and gender-specific influences on the right ventricle...
  68. pmc A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling
    Raghu S Nagalingam
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612, USA
    J Biol Chem 288:11216-32. 2013
    ..Our study demonstrates that miR-378 is an endogenous negative regulator of Ras signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy...
  69. pmc Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties
    Euy Myoung Jeong
    Department of Medicine, Section of Cardiology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
    J Mol Cell Cardiol 56:44-54. 2013
    ..These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins...
  70. pmc Integration of troponin I phosphorylation with cardiac regulatory networks
    R John Solaro
    Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    Circ Res 112:355-66. 2013
    ..We review how phosphorylation signaling to cardiac troponin I is integrated, with parallel signals controlling excitation-contraction coupling, hypertrophy, and metabolism...
  71. pmc S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding
    Jorge Alegre-Cebollada
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA Electronic address
    Cell 156:1235-46. 2014
    ..We propose that posttranslational modification of cryptic residues is a general mechanism to regulate tissue elasticity...
  72. pmc Analysing force-pCa curves
    John S Walker
    Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
    J Muscle Res Cell Motil 31:59-69. 2010
    ..The Hill coefficient was found to be sufficiently log-normally distributed that log-transformed values should be used to test for statistically significant differences...
  73. ncbi Impact of osmotic compression on sarcomere structure and myofilament calcium sensitivity of isolated rat myocardium
    Gerrie P Farman
    Dept of Physiology and Biophysics M C 901, Univ of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612, USA
    Am J Physiol Heart Circ Physiol 291:H1847-55. 2006
    ..These findings provide support for a "switch-like" activation mechanism within the cardiac sarcomere that is highly sensitive to changes in external osmotic pressure...
  74. pmc Interfilament spacing is preserved during sarcomere length isometric contractions in rat cardiac trabeculae
    Gerrie P Farman
    Center for Cardiovascular Research, Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612 7342, USA
    Biophys J 92:L73-5. 2007
    ..We conclude that the cardiac myofilament lattice maintains constant volume, and thus constant interfilament spacing, during contraction...
  75. ncbi Myofilament calcium sensitivity does not affect cross-bridge activation-relaxation kinetics
    Pieter P de Tombe
    Center for Cardiovascular Research, Univ of Illinois at Chicago, 835 S Wolcott Avenue, MC901, Chicago IL 60612, USA
    Am J Physiol Regul Integr Comp Physiol 292:R1129-36. 2007
    ..This result suggests that intrinsic cross-bridge cycling rate is not altered by the dynamics of thin-filament activation...
  76. ncbi Cardiac dysfunction and heart failure are associated with abnormalities in the subcellular distribution and amounts of oligomeric muscle LIM protein
    Samuel Y Boateng
    Dept of Physiology and Biophysics M C 901 Univ of Illinois at Chicago, 835 S Wolcott Ave, Chicago IL 60612 7342, USA
    Am J Physiol Heart Circ Physiol 292:H259-69. 2007
    ..Therefore, reduced oligomeric MLP in the costamere and cytoskeleton may contribute to impaired mechanosensing in heart failure...
  77. ncbi Identification of a region of troponin I important in signaling cross-bridge-dependent activation of cardiac myofilaments
    Patti L Engel
    Center for Cardiovascular Research, Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612, USA
    J Biol Chem 282:183-93. 2007
    ....
  78. ncbi Myofilament response to Ca2+ and Na+/H+ exchanger activity in sex hormone-related protection of cardiac myocytes from deactivation in hypercapnic acidosis
    Tepmanas Bupha-Intr
    Department of Physiology and Biophysics, Medicine and Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612 7342, USA
    Am J Physiol Regul Integr Comp Physiol 292:R837-43. 2007
    ....
  79. ncbi Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts
    Natalia Sorokina
    Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    Circulation 115:2033-41. 2007
    ....
  80. ncbi Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis
    Ganapathy Jagatheesan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0524, USA
    Am J Physiol Heart Circ Physiol 293:H949-58. 2007
    ..These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease...
  81. pmc Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium
    Regis R Lamberts
    Department of Anesthesiology, Institute for Cardiovascular Research ICaR VU, VU University Medical Center VUmc, 1081 BT Amsterdam, The Netherlands
    J Physiol 582:695-709. 2007
    ..We propose a novel role for PKC-mediated TnI phosphorylation in modulating the force-frequency relation...
  82. ncbi Correlations between alterations in length-dependent Ca2+ activation of cardiac myofilaments and the end-systolic pressure-volume relation
    Grzegorz Nowak
    Department of Medicine, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, 840 S Wood Street M C 715, Chicago, IL 60612, USA
    J Muscle Res Cell Motil 28:415-9. 2007
    ..Thus, changes in LDA should be considered in interpreting results from in situ experiments on inotropic effects associated with physiological and patho-physiological states of the heart...
  83. ncbi Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity
    Sudarsan Rajan
    Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267 0524, USA
    Circ Res 101:205-14. 2007
    ..As such, this is the first mouse model in which a mutation in a sarcomeric thin filament protein, specifically TM, leads to DCM...
  84. pmc Regulation of cardiac excitation and contraction by p21 activated kinase-1
    Yunbo Ke
    The Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, College of Medicine, Room 202, COMRB, 835 South Wolcott Avenue, Chicago, IL 60612, USA
    Prog Biophys Mol Biol 98:238-50. 2008
    ..Coordination of Pak1 and PP2A activities is not only potentially involved in regulation of normal cardiac function, but is likely to be important in patho-physiological conditions...
  85. ncbi Principal strain changes precede ventricular wall thinning during transition to heart failure in a mouse model of dilated cardiomyopathy
    Janusz H Hankiewicz
    Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, 835 South Wolcott Ave, Chicago, IL 60612, USA
    Am J Physiol Heart Circ Physiol 294:H330-6. 2008
    ..The findings indicate a near step function in E1 depression that precedes the onset of LV wall thinning and suggest E1 as a prognostic indicator of dilated cardiomyopathy...
  86. pmc Use of 2-D DIGE analysis reveals altered phosphorylation in a tropomyosin mutant (Glu54Lys) linked to dilated cardiomyopathy
    Chad M Warren
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 E Wolcott Avenue, Chicago, IL 60612, USA
    Proteomics 8:100-5. 2008
    ....
  87. pmc The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation
    R John Solaro
    Department of Physiology and Biophysics M C901 and Center for Cardiovascular Research, 835 South Wolcott Avenue, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA
    Biochem Biophys Res Commun 369:82-7. 2008
    ..A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I...
  88. doi PICOT: a multidomain scaffolding inhibitor of hypertrophic signal transduction
    Allen M Samarel
    Circ Res 102:625-7. 2008
  89. ncbi Assessment of cardiac function with the pressure-volume conductance system following myocardial infarction in mice
    Krystyna M Shioura
    The Center for Cardiovascular Research, Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL 60612, USA
    Am J Physiol Heart Circ Physiol 293:H2870-7. 2007
    ....
  90. pmc Stimulus interval, rate and direction differentially regulate phosphorylation for mechanotransduction in neonatal cardiac myocytes
    Samuel E Senyo
    Department of Bioengineering, University of Illinois at Chicago, 835 S Wolcott Avenue, Chicago, IL 60612, USA
    FEBS Lett 581:4241-7. 2007
    ..05). Mechanotransduction may have a refractory period of 5 min and differentiate directions and rates of strain...
  91. ncbi p38-MAPK induced dephosphorylation of alpha-tropomyosin is associated with depression of myocardial sarcomeric tension and ATPase activity
    Susan Vahebi
    Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave, Chicago, IL 60612 7342, USA
    Circ Res 100:408-15. 2007
    ..These data are the first to indicate that chronic activation of p38alpha MAPK directly depresses sarcomeric function in association with decreased phosphorylation of alpha-tropomyosin...
  92. ncbi Cardiac troponin I threonine 144: role in myofilament length dependent activation
    Kittipong Tachampa
    Department of Physiology and Biophysics, University of Illinois, Chicago IL 60612, USA
    Circ Res 101:1081-3. 2007
    ..24+/-0.04 micromol/L), whereas the presence of ssTnI(Pro>Thr) increased deltaEC50 to 0.94+/-0.12 micromol/L. These results suggest that Thr144 in cardiac TnI modulates cardiac myofilament length-dependent activation...

Research Grants62

  1. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  2. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  3. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  4. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  5. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  6. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  7. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  8. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  9. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  10. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  11. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  12. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  13. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..