Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome

Jelena Zlatkovic, D. Kent Arrell, Garvan M Kane, Takashi Miki, Susumu Seino, Andre Terzic

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

KCNJ11 null mutants, lacking Kir6.2 ATP-sensitive K+ (K ATP) channels, exhibit a marked susceptibility towards hypertension (HTN)-induced heart failure. To gain insight into the molecular alterations induced by knockout of this metabolic sensor under hemodynamic stress, wild-type (WT) and Kir6.2 knockout (Kir6.2-KO) cardiac proteomes were profiled by comparative 2-DE and Orbitrap MS. Despite equivalent systemic HTN produced by chronic hyperaldosteronism, 114 unique proteins were altered in Kir6.2-KO compared to WT hearts. Bioinformatic analysis linked the primary biological function of the KATP channel-dependent protein cohort to energetic metabolism (64% of proteins), followed by signaling infrastructure (36%) including oxidoreductases, stress-related chaperones, processes supporting protein degradation, transcription and translation, and cytostructure. Mapped protein-protein relationships authenticated the primary impact on metabolic pathways, delineating the KATP channel-dependent subproteome within a nonstochastic network. Iterative systems interrogation of the proteomic web prioritized heart-specific adverse effects, i.e., "Cardiac Damage", "Cardiac Enlargement", and "Cardiac Fibrosis", exposing a predisposition for the development of cardiomyopathic traits in the hypertensive Kir6.2-KO. Validating this maladaptive forecast, phenotyping documented an aggravated myocardial contractile performance, a massive interstitial fibrosis and an exaggerated left ventricular size, all prognostic indices of poor outcome. Thus, Kir6.2 ablation engenders unfavorable proteomic remodeling in hypertensive hearts, providing a composite molecular substrate for pathologic stress-associated cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)1314-1325
Number of pages12
JournalProteomics
Volume9
Issue number5
DOIs
StatePublished - Mar 2009

Fingerprint

KATP Channels
Proteomics
Proteins
Fibrosis
Hypertension
Hyperaldosteronism
Protein Biosynthesis
Proteome
Metabolic Networks and Pathways
Computational Biology
Proteolysis
Hemodynamics
Transcription
Bioinformatics
Ablation
Oxidoreductases
Metabolism
Cardiovascular Diseases
Heart Failure
Adenosine Triphosphate

Keywords

  • ATP-sensitive K channel
  • Bioinformatics
  • Heart failure
  • Kir6.2
  • Systems biology

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry

Cite this

Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome. / Zlatkovic, Jelena; Arrell, D. Kent; Kane, Garvan M; Miki, Takashi; Seino, Susumu; Terzic, Andre.

In: Proteomics, Vol. 9, No. 5, 03.2009, p. 1314-1325.

Research output: Contribution to journalArticle

Zlatkovic, Jelena ; Arrell, D. Kent ; Kane, Garvan M ; Miki, Takashi ; Seino, Susumu ; Terzic, Andre. / Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome. In: Proteomics. 2009 ; Vol. 9, No. 5. pp. 1314-1325.
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