ATP-sensitive K+ channel knockout induces cardiac proteome remodeling predictive of heart disease susceptibility
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Updated: Jun 21, 2026
Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
D Kent Arrell1, Jelena Zlatkovic, Garvan C Kane
1Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Abstract:
Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (K(ATP)) 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. High-throughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 K(ATP) channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved >800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. K(ATP) 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 K(ATP) 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 K(ATP) channel-associated subproteome within a nonstochastic scale-free network. Global assessment of the K(ATP) 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 K(ATP) channel deletion, establishing a systems approach that predicts outcome at a presymptomatic stage.
Insights
Forecasting cardiac disease requires identifying early molecular changes. Proteomic analysis of Kir6.2 knockout hearts revealed significant metabolic remodeling, predicting future cardiovascular disease and poor outcomes.
Area of Science:
- Cardiovascular Proteomics
- Systems Biology
- Channelopathies
Background:
- Predicting disease susceptibility necessitates identifying preclinical molecular indicators.
- Cardiac ATP-sensitive K+ (K(ATP)) channelopathies, specifically those involving Kir6.2, lack identified substrates for disease vulnerability.
- Understanding molecular pathobiology of genetic defects requires robust systems platforms for diagnosing predisposition.
Purpose of the Study:
- To decode the molecular consequences of Kir6.2 K(ATP) channel pore deletion using integrated proteomic and network biology approaches.
- To identify presymptomatic molecular signatures of disease susceptibility in cardiac channelopathies.
- To establish a systems approach for predicting disease outcome at a presymptomatic stage.
Main Methods:
- High-throughput proteomic analysis using differential two-dimensional gel electrophoresis and hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry.
- Network biology and protein interaction mapping to analyze the cardiac proteome in wild-type and Kir6.2-knockout mice.
- Ontological annotation to stratify protein cohorts and assess pathway enrichment.
Main Results:
- K(ATP) channel ablation significantly remodeled the cardiac proteome, altering 71 protein spots (102 unique identities).
- The K(ATP) channel-dependent proteome was predominantly enriched in bioenergetic pathways, with additional alterations in signaling, oxidoreductases, chaperones, catabolism, cytostructure, and transcription/translation.
- Network analysis localized a K(ATP) channel-associated subproteome within a scale-free network, confirming a primary impact on metabolic pathways and revealing cardiovascular disease markers.
Conclusions:
- Proteomic cartography provides an integral view of cardiac molecular remodeling induced by K(ATP) channel deletion.
- The study establishes a systems biology approach to predict disease susceptibility and outcome at a presymptomatic stage.
- Kir6.2 knockout hearts exhibit exaggerated defects under stress, validating the predictive power of proteomic profiling for disease forecasting.
