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Proteomic profiling of K ATP channel‐deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcome
Author(s) -
Zlatkovic Jelena,
Arrell D. Kent,
Kane Garvan C.,
Miki Takashi,
Seino Susumu,
Terzic Andre
Publication year - 2009
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.200800718
Subject(s) - medicine , heart failure , cardiac fibrosis , proteome , endocrinology , cardiology , bioinformatics , biology
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.