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

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

Research output: Contribution to journalArticle

33 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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