H11 has dose-dependent and dual hypertrophic and proapoptotic functions in cardiac myocytes

Abstract

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.

Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival

“…17 In that condition, H11K overexpression still increased Smad phosphorylation ( Figure 2E). We showed before that H11-KI also activates the PI3K/Akt pathway, 17 indicating that the activation of both BMP and PI3K/Akt pathways is performed by the chaperone function, rather than by the kinase function, of H11K.…”

“…6 The cytoprotective effects, mediated by the PI3K/Akt pathway, are observed when H11K protein expression increases by 3-to 5-fold, which is found in vivo across species, such as dog, swine and humans, in both conditions of myocardial growth 2 and ischemia, 4 and in our TG model. 2,5 Reciprocally, proapoptotic effects occur in cell culture 17 through the activation of p38 MAPK when H11K is excessively overloaded. We show that the prosurvival versus prodeath effects of H11K crucially depend on the balance between TAK1, p38 MAPK and Akt activity.…”

“…We showed before that inhibition of PI3K also blocks the growth-promoting effect of H11K. 17 Therefore, an active BMP/PI3K axis dictates the physiological effects of H11K on cardiac cell growth and survival.…”

“…18 This paradox reflects the dual properties of H11K, which promotes survival at physiological concentrations in vivo but promotes apoptosis on excessive overload in vitro. 17 Therefore, we determined whether TAK1 interacts with H11K in the heart, and whether TAK1 affects p38 MAPK and Akt activities in our model. The interaction of TAK1 with the BMP receptors and with H11K was tested in vivo.…”

Abnormal interaction of motor neuropathy-associated mutant HspB8 (Hsp22) forms with the RNA helicase Ddx20 (gemin3)

“…1a). Most of the studied sHSPs have chaperone-like properties that are thought to be the basis for their ability to protect cells from adverse conditions by inhibiting apoptosis (Rogalla et al 1999;Bruey et al 2000;Kim et al 2004;Carra et al 2005), although HspB8 may act also through a non-canonical mechanism which is unrelated to the chaperone model, and may even promote apoptosis (Hase et al 2005;Carra et al 2009). sHSPs have been implicated in various additional functions, including consolidation of redox homeostasis, proteasome-mediated protein degradation, RNA processing, and cytoskeletal functions such as cell motility, and muscle contraction and relaxation (reviewed in Benndorf 2010).…”