ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility

D. Kent Arrell, Jelena Zlatkovic, Garvan M Kane, Satsuki Yamada, Andre Terzic

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. Highthroughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved >800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scalefree network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems approach that predicts outcome at a presymptomatic stage.

Original languageEnglish (US)
Pages (from-to)4823-4834
Number of pages12
JournalJournal of Proteome Research
Volume8
Issue number10
DOIs
StatePublished - 2009

Fingerprint

KATP Channels
Disease Susceptibility
Proteome
Heart Diseases
Adenosine Triphosphate
Proteins
Proteomics
Protein Interaction Mapping
Channelopathies
Defects
Electrophoresis, Gel, Two-Dimensional
Transcription
Tandem Mass Spectrometry
Systems Analysis
Ablation
Metabolic Networks and Pathways
Electrophoresis
Energy Metabolism
Mass spectrometry
Oxidoreductases

Keywords

  • Channelopathy
  • Individualized medicine
  • K channel
  • KCNJ11
  • Kir6.2
  • Network
  • Predictive medicine
  • Proteomics
  • Systems biology

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Cite this

ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility. / Arrell, D. Kent; Zlatkovic, Jelena; Kane, Garvan M; Yamada, Satsuki; Terzic, Andre.

In: Journal of Proteome Research, Vol. 8, No. 10, 2009, p. 4823-4834.

Research output: Contribution to journalArticle

@article{a7bcc1ee923c46ae947456cbb6ef0540,
title = "ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility",
abstract = "Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. Highthroughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved >800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scalefree network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems approach that predicts outcome at a presymptomatic stage.",
keywords = "Channelopathy, Individualized medicine, K channel, KCNJ11, Kir6.2, Network, Predictive medicine, Proteomics, Systems biology",
author = "Arrell, {D. Kent} and Jelena Zlatkovic and Kane, {Garvan M} and Satsuki Yamada and Andre Terzic",
year = "2009",
doi = "10.1021/pr900561g",
language = "English (US)",
volume = "8",
pages = "4823--4834",
journal = "Journal of Proteome Research",
issn = "1535-3893",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility

AU - Arrell, D. Kent

AU - Zlatkovic, Jelena

AU - Kane, Garvan M

AU - Yamada, Satsuki

AU - Terzic, Andre

PY - 2009

Y1 - 2009

N2 - Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. Highthroughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved >800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scalefree network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems approach that predicts outcome at a presymptomatic stage.

AB - Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. Highthroughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved >800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scalefree network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems approach that predicts outcome at a presymptomatic stage.

KW - Channelopathy

KW - Individualized medicine

KW - K channel

KW - KCNJ11

KW - Kir6.2

KW - Network

KW - Predictive medicine

KW - Proteomics

KW - Systems biology

UR - http://www.scopus.com/inward/record.url?scp=70349972372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349972372&partnerID=8YFLogxK

U2 - 10.1021/pr900561g

DO - 10.1021/pr900561g

M3 - Article

VL - 8

SP - 4823

EP - 4834

JO - Journal of Proteome Research

JF - Journal of Proteome Research

SN - 1535-3893

IS - 10

ER -