title: Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome.
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 K(ATP) 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 K(ATP) 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.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Zlatkovic
authors.forename: D Kent
authors.initials: DK
authors.lastname: Arrell
authors.forename: Garvan C
authors.initials: GC
authors.lastname: Kane
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications / Q000209:etiology; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D054086:KATP Channels / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025941:Protein Interaction Mapping; D020543:Proteome / Q000032:analysis* / Q000235:genetics / Q000378:metabolism
chemical_list: D054086:KATP Channels; D020543:Proteome