K_ATP channel-dependent metaboproteome decoded: Systems approaches to heart failure prediction, diagnosis, and therapy

Systems biology provides an integrative platform by which to account for the biological complexity related to cardiac health and disease. In this way, consequences of ATP-sensitive K⁺ (K_ATP) channel deficiency for heart failure prediction, diagnosis, and therapy were resolved recently at a proteomic level. Under stress-free conditions, knockout of the Kir6.2 K _ATP channel pore induced metabolic proteome remodelling, revealing overrepresentation of markers of cardiovascular disease. Imposed stress precipitated structural and functional defects in Kir6.2-knockout hearts, decreasing survival and validating prediction of disease susceptibility. In the setting of hypertension, a leading risk for heart failure development, proteomic analysis diagnosed the metabolism-centric impact of K_ATP channel deficiency in disease. Bioinformatic interrogation of K_ATP channel-dependent proteome prioritized heart-specific adverse effects, exposing cardiomyopathic traits of aggravated contractility, fibrosis, and ventricular hypertrophy. In dilated cardiomyopathy induced by Kir6.2-knockout pressure overload, proteomic remodelling was exacerbated, underlying a multifaceted molecular pathology that indicates the necessity for a broad-based strategy to achieve repair. Embryonic stem cell intervention in cardiomyopathic K _ATP channel knockout hearts elicited a distinct proteome signature that forecast amelioration of adverse cardiac outcomes. Functional/structural measurements validated improved contractile performance, reduced ventricular size, and decreased cardiac damage in the treated cohort, while systems assessment unmasked cardiovascular development as a prioritized biological function in stem cell-reconstructed hearts. Thus, proteomic deconvolution of K_ATP channel-deficient hearts provides definitive evidence for the channels homeostatic contribution to the cardiac metaboproteome and establishes the utility of systems-oriented approaches to predict disease susceptibility, diagnose consequences of heart failure progression, and monitor therapy outcome.