Abstract 213: H11 Kinase Promotes Cardiac Cell Growth and Survival Through an mTOR-Mediated Activation of the Phosphatidylinositol-3-Kinase Pathway
The chaperone H11 Kinase (H11K) accumulates in both conditions of myocardial ischemia and pressure overload. Cardiac-specific over-expression (7-fold) of H11K in transgenic (TG) mice confers ischemic cardioprotection and promotes cardiac hypertrophy. We tested the role of phosphatidylinositol-3-kinase (PI-3K) in the effects of H11K on cardiac survival and growth. PI-3K activity increased by 3-fold (P<0.05) in hearts from TG vs wild type (WT), together with an increased (P<0.05) phosphorylation of PI-3K effectors (Akt, PKCe, mTOR). In TG, H11K accumulated at the nuclear membrane, where it attracted and interacted with PI-3K, Akt and mTOR. The TG showed a 2-fold increased expression (P<0.05 vs WT) of the transcription factor Egr-1. The IGF-1 receptor (IGF-R), an activator of PI-3K, increased by 3-fold in TG (P<0.05 vs WT) and translocated to the plasma membrane. Treatment of mice with the mTOR inhibitor rapamycin (2 mg/kg daily) abolished mTOR activity, dissociated the nuclear PI-3K/mTOR complex, redistributed these kinases into the cytosol, and decreased the expression of Egr-1 and IGF-R by 60% (P<0.01 vs vehicle). Rapamycin suppressed the cardioprotection (infarct size/area at risk: vehicle-36±5 in WT vs 4.0±0.5 in TG, P<0.01; rapamycin-38±4 in WT vs 33±4 in TG, NS) and decreased by 50% the hypertrophy in TG hearts (heart weight/tibial length: vehicle-7.3±0.2 in WT vs 10.4±0.2 in TG, P<0.01; rapamycin-7.1±0.2% in WT vs 8.7±0.2% in TG, P<0.05). In C2C12 myoblasts, over-expression of Egr-1 was sufficient to increase IGF-R expression, whereas rapamycin decreased the expression of both Egr-1 and IGF-R. Therefore, H11K over-expression builds a nuclear PI-3K/mTOR complex stimulating the transcription factor Egr-1, leading to increased expression and translocation of IGF-R, thereby maintaining the PI-3K pathway active. Blocking this mechanism by mTOR inhibition prevents the effects of H11K on cardiac survival and growth.