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H11 Kinase promotes a genomic program of metabolic survival in the heart
Author(s) -
Wang Li,
Qiu Hongyu,
Chen Li,
Depre Christophe
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1189-c
Subject(s) - ampk , protein kinase b , pi3k/akt/mtor pathway , protein kinase a , nrf1 , amp activated protein kinase , chemistry , cardioprotection , microbiology and biotechnology , phosphorylation , medicine , endocrinology , biology , signal transduction , mitochondrion , mitochondrial biogenesis , ischemia
H11 Kinase (H11K) is a heat‐shock protein accumulating in heart from patients with heart disease. This increase was reproduced in a cardiac‐specific transgenic (TG) mouse model, which results in a cardioprotection equivalent to ischemic preconditioning. Such protection is associated with the activation of two survival pathways, Akt and the 5′AMP‐activated protein kinase (AMPK). However, Akt and AMPK have opposite effects on cell growth through a reciprocal regulation of mTOR. Therefore, in this study, we tested the hypothesis that the respective role of Akt and AMPK in cell growth versus survival is related to their subcellular distribution. Hearts from TG mice showed an increased phosphorylation of Akt by 3‐fold and of AMPK by 2‐fold (both, P<0.05 vs WT). Subcellular fractionation showed a 4‐fold accumulation of both enzymes in the nuclear fraction of TG hearts (P<0.01 vs WT). Immunoprecipitation showed that H11K interacts with both Akt and AMPK in the nuclear fraction and promotes their interaction into a nuclear multi‐protein complex. No interaction between Akt and AMPK was found in the cytosol. Hypoxia‐inducible factor 1α (HIF‐1α), a transcription factor activated by both Akt and AMPK, was increased 5‐fold in nuclear fractions from TG hearts (P<0.01 vs WT). Mouse micro‐arrays were performed, showing a significant upregulation of HIF‐1α‐regulated genes in TG hearts: glycogen metabolism, glucose transport and glycolysis, as well as VEGF, inducible NOS, heme oxygenase and IGFBP3. Therefore, increased expression of H11K activates Akt and AMPK but also promotes the nuclear translocation and physical interaction of both molecules, followed by activation of HIF‐1α and a genomic profile of metabolic survival. By redistributing the kinases between subcellular compartments, H11K turns the antagonism between Akt and AMPK on cell growth into cooperation for cell survival.