ATP-sensitive K+ channel-deficient dilated cardiomyopathy proteome remodeled by embryonic stem cell therapy

Jelena Zlatkovic-Lindor, D. Kent Arrell, Satsuki Yamada, Timothy J Nelson, Andre Terzic

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1355-1367
Number of pages13
JournalStem Cells
Volume28
Issue number8
DOIs
StatePublished - Aug 2010

Fingerprint

Dilated Cardiomyopathy
Proteome
Embryonic Stem Cells
Cell- and Tissue-Based Therapy
Stem Cells
Adenosine Triphosphate
Heart Failure
Inwardly Rectifying Potassium Channel
Biological Phenomena
Therapeutics
Pluripotent Stem Cells
Proteins
Genetic Models
Electrophoresis, Gel, Two-Dimensional
Stem Cell Transplantation
Systems Analysis
Computational Biology
Proteomics
Proteolysis
Mass Spectrometry

Keywords

  • ATP-sensitive K channel
  • Bioinformatics
  • Dilated cardiomyopathy
  • Genetics
  • K channel
  • Networks
  • Protein expression
  • Proteomics
  • Regenerative medicine

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

ATP-sensitive K+ channel-deficient dilated cardiomyopathy proteome remodeled by embryonic stem cell therapy. / Zlatkovic-Lindor, Jelena; Arrell, D. Kent; Yamada, Satsuki; Nelson, Timothy J; Terzic, Andre.

In: Stem Cells, Vol. 28, No. 8, 08.2010, p. 1355-1367.

Research output: Contribution to journalArticle

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