H11 has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes.
We have shown previously that H11, a serine/threonine kinase, is up-regulated in a heart subjected to ischaemia/reperfusion. In the present study, we have characterized the cellular function of H11, using neonatal rat cardiac myocytes. Although transduction of adenovirus harbouring H11 at low doses increased the cell size, at higher doses it induced apoptosis in cardiac myocytes. Apoptosis was not observed when adenovirus harbouring H11-KI (kinase-inactive mutant of H11) was used, suggesting that the proapoptotic effect of H11 is kinase-dependent. The hypertrophic effect of H11 at high doses was unmasked when apoptosis was inhibited by the caspase inhibitor DEVD-CHO, suggesting that H11 stimulates both hypertrophy and apoptosis in parallel. H11-KI induced hypertrophy even at high doses, indicating that H11 stimulates hypertrophy through kinase-independent mechanisms. H11-KI activated Akt, and cardiac hypertrophy induced by H11-KI was blocked by LY294002, an inhibitor of phosphoinositide 3-kinase. Co-immunoprecipitation analyses indicated that H11 interacts with the alpha subunit of CK2 (casein kinase 2). Overexpression of H11 decreased the kinase activity of CK2. DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole), an inhibitor of CK2, mimicked the effect of H11, whereas DRB and H11 failed to exhibit additive effects on apoptosis, suggesting that H11 and DRB utilize a common mechanism to induce apoptosis, namely inhibition of CK2. In summary, H11 is a dual-function kinase in cardiac cells: it induces hypertrophy at low doses through kinase-independent activation of Akt, whereas it causes apoptosis at high doses through protein kinase-dependent mechanisms, in particular by physical interaction with and subsequent inhibition of CK2.
Hase
Makoto
M
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ, USA.
Depre
Christophe
C
Vatner
Stephen F
SF
Sadoshima
Junichi
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D047390:Casein Kinase II / Q000378:metabolism; D049108:Cell Enlargement; D002478:Cells, Cultured; D018628:Gene Dosage; D005786:Gene Expression Regulation; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins; D015398:Signal Transduction
C504813:H11 protein, rat; D009124:Muscle Proteins; D011994:Recombinant Proteins; D047390:Casein Kinase II