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Regulation of PKC isoforms by H11 Kinase in the heart
Author(s) -
Sui Xiangzhen,
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.a1190-a
Subject(s) - protein kinase c , wortmannin , gene isoform , phosphorylation , medicine , cardioprotection , endocrinology , pkc alpha , chemistry , phosphatidylinositol , microbiology and biotechnology , biology , biochemistry , ischemia , gene
The small heat shock protein H11 Kinase (H11K) accumulates in myocardium of patients with ischemic heart disease. Increased expression of H11K in a cardiac‐specific transgenic (TG) mouse provides cardioprotection equivalent to ischemic preconditioning (PC). Because of the predominant role of PKC (especially the epsilon isoform) in PC, we tested whether the cardioprotective effect of H11K involves a regulation of PKC isoforms. In hearts from TG compared to wild type (WT), there was a significant (P<0.05) increase in expression (40%), phosphorylation (2‐fold) and activity (50%) of both PKC alpha and epsilon. Both enzymes showed a 70% increase in translocation from the soluble to the particulate fraction in TG vs WT (P<0.01). Reciprocally, PKC isoforms delta and zeta did not show significant change. Interaction of PKC epsilon and alpha with the chaperone HSP70, as measured by co‐immunoprecipitation, was markedly increased in TG vs WT, which is known to stabilize active PKC and may therefore explain the increase in PKC expression and phosphorylation. Treatment of TG mice with wortmannin (3 mg/kg daily for five days), an inhibitor of phosphatidylinositol 3‐kinase (PI3K) totally abolished both the activation and translocation of PKC alpha and epsilon. When submitted to coronary occlusion/ reperfusion, apoptosis, as measured by the percentage of TUNEL‐positive myocytes, was 1.0±0.1% in WT and 0.4±0.05% in TG (60% reduction in TG vs WT, P<0.01). After wortmannin treatment, protection in TG mice was totally lost. Therefore, H11K overexpression in the heart promotes the activation and translocation of both PKC alpha and epsilon in a PI3K‐dependent mechanism. Inhibition of this pathway prevents the anti‐apoptotic cardioprotection by H11K, suggesting an essential role for PKC in this protection.