Key result
Kir6.2 K(ATP) channel deletion remodeled the cardiac proteome, significantly altering 71 protein spots, and decreased survivorship under graded stress compared to wild-type counterparts.
Why the study?
Does Kir6.2 K(ATP) channel deletion induce cardiac proteome remodeling predictive of heart disease susceptibility in preclinical models?
Does Kir6.2 K(ATP) channel deletion induce cardiac proteome remodeling predictive of heart disease susceptibility in preclinical models?
Kir6.2 K(ATP) channel deletion induces significant cardiac proteome remodeling, primarily in metabolic pathways, which predicts increased susceptibility to heart disease under stress.
Hypothesis-generating in mice; leaves open whether Kir6.2 deletion or proteome changes predict human cardiac stress susceptibility.
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.
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Arrell et al. (2009) studied Cardiac ATP-sensitive K+ (K(ATP)) channelopathies. Kir6.2 K(ATP) channel pore deletion vs. Wild-type counterparts was evaluated on Cardiac proteome remodeling and survivorship under graded stress. Kir6.2 K(ATP) channel deletion remodeled the cardiac proteome, significantly altering 71 protein spots, and decreased survivorship under graded stress compared to wild-type counterparts.
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