ATP‐Sensitive K+ Channel‐Deficient Dilated Cardiomyopathy Proteome Remodeled by Embryonic Stem Cell Therapy

Transplantation of pluripotent stem cells has proven beneficial in heart failure, yet the proteomic landscape underlying repair remains largely uncharacterized. In a genetic model of dilated cardiomyopathy elicited by pressure overload in the KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11) null mutant, proteome‐wide profiles were here resolved by means of a systems approach prior to and following disease manifestation in the absence or presence of embryonic stem cell treatment. Comparative two‐dimensional gel electrophoresis revealed a unique cardiomyopathic proteome in the absence of therapy, remodeled in response to stem cell treatment. Specifically, linear ion trap quadrupole‐Orbitrap mass spectrometry determined the identities of 93 and 109 differentially expressed proteins from treated and untreated cardiomyopathic hearts, respectively. Mapped protein–protein relationships and corresponding neighborhoods incorporated the stem cell‐dependent subproteome into a nonstochastic network with divergent composition from the stem cell‐independent counterpart. Stem cell intervention produced a distinct proteome signature across a spectrum of biological processes ranging from energetic metabolism, oxidoreductases, and stress‐related chaperones to processes supporting protein synthesis/degradation, signaling, and transport regulation, cell structure and scaffolding. In the absence of treatment, bioinformatic interrogation of the disease‐only proteome network prioritized adverse cardiac outcomes, ablated or ameliorated following stem cell transplantation. Functional and structural measurements validated improved myocardial contractile performance, reduced ventricular size and decreased cardiac damage in the treated cohort. Unbiased systems assessment unmasked “cardiovascular development” as a prioritized biological function in stem cell‐reconstructed cardiomyopathic hearts. Thus, embryonic stem cell treatment transformed the cardiomyopathic proteome to demote disease‐associated adverse effects and sustain a procardiogenic developmental response, supplying a regenerative substrate for heart failure repair. STEM CELLS 2010;28:1355–1367

[1]  D. K. Arrell,et al.  Network Systems Biology for Drug Discovery , 2010, Clinical pharmacology and therapeutics.

[2]  João Ferreira-Martins,et al.  Anthracycline Cardiomyopathy Is Mediated by Depletion of the Cardiac Stem Cell Pool and Is Rescued by Restoration of Progenitor Cell Function , 2010, Circulation.

[3]  A. Lusis,et al.  Cardiovascular networks: systems-based approaches to cardiovascular disease. , 2010, Circulation.

[4]  A. Terzic,et al.  Human KATP channelopathies: diseases of metabolic homeostasis , 2009, Pflügers Archiv - European Journal of Physiology.

[5]  Kenneth R Chien,et al.  Regeneration next: toward heart stem cell therapeutics. , 2009, Cell stem cell.

[6]  Gary D Bader,et al.  How to visually interpret biological data using networks , 2009, Nature Biotechnology.

[7]  B. Gersh,et al.  Cardiac cell repair therapy: a clinical perspective. , 2009, Mayo Clinic proceedings.

[8]  Timothy J. Nelson,et al.  iPS Programmed Without c-MYC Yield Proficient Cardiogenesis for Functional Heart Chimerism , 2009, Circulation research.

[9]  D. K. Arrell,et al.  ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility. , 2009, Journal of proteome research.

[10]  R. Aebersold,et al.  Applying mass spectrometry-based proteomics to genetics, genomics and network biology , 2009, Nature Reviews Genetics.

[11]  Bruce D. Johnson,et al.  KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response , 2009, Human Genetics.

[12]  Timothy J. Nelson,et al.  Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. , 2009, Circulation.

[13]  M. Asakura,et al.  Global gene expression profiling in the failing myocardium. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[14]  Timothy J. Nelson,et al.  Stem Cell Transplant into Preimplantation Embryo Yields Myocardial Infarction‐Resistant Adult Phenotype , 2009, Stem cells.

[15]  Timothy J. Nelson,et al.  Stem Cell Platforms for Regenerative Medicine , 2009, Clinical and translational science.

[16]  Ana Morales,et al.  Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. , 2009, Circulation. Heart failure.

[17]  D. K. Arrell,et al.  Proteomic profiling of KATP channel‐deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome , 2009, Proteomics.

[18]  Peipei Ping,et al.  Getting to the heart of proteomics. , 2009, The New England journal of medicine.

[19]  J. Butany,et al.  Dilated cardiomyopathy: a review , 2008, Journal of Clinical Pathology.

[20]  Samuel Bernard,et al.  Evidence for Cardiomyocyte Renewal in Humans , 2008, Science.

[21]  Timothy J. Nelson,et al.  Embryonic Stem Cell Therapy of Heart Failure in Genetic Cardiomyopathy , 2008, Stem cells.

[22]  M. Disatnik,et al.  Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart , 2008, Science.

[23]  C. Mummery,et al.  Proteomics and human embryonic stem cells. , 2008, Stem cell research.

[24]  Timothy J. Nelson,et al.  Strategies for Therapeutic Repair: The “R3” Regenerative Medicine Paradigm , 2008, Clinical and translational science.

[25]  R. Passier,et al.  Stem-cell-based therapy and lessons from the heart , 2008, Nature.

[26]  C. Bearzi,et al.  The Human Heart: A Self‐Renewing Organ , 2008, Clinical and translational science.

[27]  A. Terzic,et al.  Therapeutic Targeting: A Crucible for Individualized Medicine , 2008, Clinical pharmacology and therapeutics.

[28]  Richard T. Lee,et al.  Stem-cell therapy for cardiac disease , 2008, Nature.

[29]  D. K. Arrell,et al.  Cardioinductive Network Guiding Stem Cell Differentiation Revealed by Proteomic Cartography of Tumor Necrosis Factor α‐Primed Endodermal Secretome , 2008, Stem cells.

[30]  Fidel Ramírez,et al.  Computing topological parameters of biological networks , 2008, Bioinform..

[31]  Michael L. Creech,et al.  Integration of biological networks and gene expression data using Cytoscape , 2007, Nature Protocols.

[32]  A. Barabasi,et al.  Drug—target network , 2007, Nature Biotechnology.

[33]  S. Matsuoka,et al.  Flk1(+) cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model. , 2007, Cardiovascular research.

[34]  D. K. Arrell,et al.  Pharmacoproteomics: Advancing the Efficacy and Safety of Regenerative Therapeutics , 2007, Clinical pharmacology and therapeutics.

[35]  Lila R Collins,et al.  Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts , 2007, Nature Biotechnology.

[36]  H. Watkins,et al.  Reviews of translational medicine and genomics in cardiovascular disease: new disease taxonomy and therapeutic implications cardiomyopathies: therapeutics based on molecular phenotype. , 2007, Journal of the American College of Cardiology.

[37]  Stefan Neubauer,et al.  The failing heart--an engine out of fuel. , 2007, The New England journal of medicine.

[38]  D. K. Arrell,et al.  Cardiopoietic programming of embryonic stem cells for tumor-free heart repair , 2007, The Journal of experimental medicine.

[39]  Andre Terzic,et al.  Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells , 2007, Nature Clinical Practice Cardiovascular Medicine.

[40]  R. Markwald,et al.  The next frontier in cardiovascular developmental biology—an integrated approach to adult disease? , 2007, Nature Clinical Practice Cardiovascular Medicine.

[41]  A. Terzic,et al.  Protection conferred by myocardial ATP‐sensitive K+ channels in pressure overload‐induced congestive heart failure revealed in KCNJ11 Kir6.2‐null mutant , 2006, The Journal of physiology.

[42]  Peipei Ping,et al.  Cardiovascular proteomics: tools to develop novel biomarkers and potential applications. , 2006, Journal of the American College of Cardiology.

[43]  Ralf Kettenhofen,et al.  Engraftment of engineered ES cell–derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium , 2006, The Journal of experimental medicine.

[44]  A. Terzic,et al.  KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension. , 2006, Human molecular genetics.

[45]  B. Rothermel,et al.  Molecular Mechanisms of Cardiac Hypertrophy and Failure , 2006 .

[46]  Roberto Bolli,et al.  Life and Death of Cardiac Stem Cells: A Paradigm Shift in Cardiac Biology , 2006, Circulation.

[47]  D. Torella,et al.  Resident human cardiac stem cells: role in cardiac cellular homeostasis and potential for myocardial regeneration , 2006, Nature Clinical Practice Cardiovascular Medicine.

[48]  T. Olson.  Monogenic dilated cardiomyopathy , 2005 .

[49]  Emmanuel Messas,et al.  Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study , 2005, The Lancet.

[50]  Christine E Seidman,et al.  The genetic basis for cardiac remodeling. , 2005, Annual review of genomics and human genetics.

[51]  A. Terzic,et al.  Cardiac KATP channels in health and disease. , 2005, Journal of molecular and cellular cardiology.

[52]  Stefanie Dimmeler,et al.  Unchain my heart: the scientific foundations of cardiac repair. , 2005, The Journal of clinical investigation.

[53]  Michael E Phelps,et al.  Systems Biology and New Technologies Enable Predictive and Preventative Medicine , 2004, Science.

[54]  Rona Shofti,et al.  Electromechanical integration of cardiomyocytes derived from human embryonic stem cells , 2004, Nature Biotechnology.

[55]  A. Terzic,et al.  Stable benefit of embryonic stem cell therapy in myocardial infarction. , 2004, American journal of physiology. Heart and circulatory physiology.

[56]  J. Bell.  Predicting disease using genomics , 2004, Nature.

[57]  Yuan-Ping Pang,et al.  ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating , 2004, Nature Genetics.

[58]  Leroy Hood,et al.  Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. , 2004, Journal of proteome research.

[59]  Z. Oltvai,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[60]  Mark E. J. Newman,et al.  The Structure and Function of Complex Networks , 2003, SIAM Rev..

[61]  J. Towbin,et al.  The failing heart , 2002, Nature.

[62]  R. Albert,et al.  The large-scale organization of metabolic networks , 2000, Nature.

[63]  K. Chien.  Genomic circuits and the integrative biology of cardiac diseases , 2000, Nature.

[64]  A. Terzic,et al.  Failing energetics in failing hearts , 2000, Current cardiology reports.

[65]  D. N. Perkins,et al.  Probability‐based protein identification by searching sequence databases using mass spectrometry data , 1999, Electrophoresis.

[66]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[67]  K. Chien,et al.  Stress Pathways and Heart Failure , 1999, Cell.

[68]  J. Yates,et al.  Direct analysis of protein complexes using mass spectrometry , 1999, Nature Biotechnology.

[69]  G. Novo,et al.  Biomarkers in heart failure. , 2009, Frontiers in bioscience.

[70]  D. K. Arrell,et al.  Embryonic stem cell cardiac differentiation : a proteomic perspective , 2007 .

[71]  C. Lovegrove.  Unmasking unexplained cardiac arrest: use of epinephrine and procainamide infusions , 2006, Nature Clinical Practice Cardiovascular Medicine.

[72]  A. Andrew,et al.  Emergence of Scaling in Random Networks , 1999 .

[73]  A. Andrew,et al.  Emergence of Scaling in Random Networks , 2022 .