期刊
PROTEOMICS
卷 9, 期 5, 页码 1314-1325出版社
WILEY-BLACKWELL
DOI: 10.1002/pmic.200800718
关键词
ATP-sensitive K+ channel; Bioinformatics; Heart failure; Kir6.2; Systems biology
资金
- National Institutes of Health
- Marriott Heart Disease Research Program
- Marriott Foundation
- Ted Nash Long Life Foundation
- Japanese Ministry of Education, Science, Sports, Culture and Technology
KCNJ11 null mutants, lacking Kir6.2 ATP-sensitive K+ (KATp) 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 KATp 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 KATp 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.
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