H11 Kinase Is a Novel Mediator of Myocardial Hypertrophy In Vivo

Abstract

By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy. Because this gene has not been characterized in the heart, the goal of the present study was to determine the function of H11 kinase in cardiac tissue, both in vitro and in vivo. In isolated neonatal rat cardiac myocytes, adenoviral-mediated overexpression of H11 kinase resulted in a 37% increase in protein/DNA ratio, reflecting hypertrophy. A cardiac-specific transgene driven by the alphaMHC-promoter was generated, which resulted in an average 7-fold increase in H11 kinase protein expression. Transgenic hearts were characterized by a 30% increase of the heart weight/body weight ratio, by the reexpression of a fetal gene program, and by concentric hypertrophy with preserved contractile function at echocardiography. This phenotype was accompanied by a dose-dependent activation of Akt/PKB and p70(S6) kinase, whereas the MAP kinase pathway was unaffected. Thus, H11 kinase represents a novel mediator of cardiac cell growth and hypertrophy.

Phenotype of Cardiomyopathy in Cardiac-specific Heat Shock Protein B8 K141N Transgenic Mouse

“…A previous study showed that overexpression of wild-type HSPB8/H11 kinase resulted in cardiac hypertrophy in mice (23). In contrast, our previous study (12), as well as the present study, showed that no obvious phenotype is observed by overexpression of HSPB8 in the heart.…”

“…Cardiac toxicity of the mutant HSPB8 was also detected in TG mice in our study. Because the cardiac HSPB8 expression level is higher than in most other human tissues (8,22,23) and because this expression pattern is similar to the results obtained in mice in the present study, these results imply that the HSPB8 missense mutations, such as K141N and K141E, are present in cardiomyocytes and peripheral neuronal cells. HSPB8 K141N protein overexpression using an ␣-myosin heavy chain promoter can cause aggresomal accumulation and amyloid formation in cardiomyocytes without any modification of noncardiomyocytes.…”

“…These in vivo and in vitro results indicate that the immunoreactivity against the anti-oligomer antibody is somewhat dissociated from the cellular toxicity. Another study also suggested that immunoreactivity against an anti-oligomer antibody is observed in native wild-type HSPs, such as human HSP27, HSP40, HSP70, HSP90, yeast HSP104, and bovine Hsc70 (23). Thus, anti-oligomer antibody immunoreactivity can be present in native proteins, particularly HSPs.…”

Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box m1 transcription factor

“…Interestingly, we observed normal cardiac expression of calmodulin, H11 kinase, serotonin 5-HT 2B receptor, and FoxO3a transcription factor (Fig. 4), all of which are essential for the development of hypertrophy in cardiomyocytes (Nebigil et al, 2000;Depre et al, 2002;Colomer et al, 2004;Skurk et al, 2005).…”

Cardiac H11 kinase/Hsp22 stimulates oxidative phosphorylation and modulates mitochondrial reactive oxygen species production: Involvement of a nitric oxide-dependent mechanism

“…A transgenic (TG) mouse with cardiac-specific over-expression of Hsp22 was generated to reproduce the increased expression found in patients [5]. The molecular characteristics of the TG mouse reproduce many hallmarks of IPC, including an activation of cell survival pathways, up-regulation of heat shock proteins, inhibition of pro-apoptotic proteins, metabolic adaptation and stimulation of growth pathways [6][7][8][9][10].…”