Abstract 12711: Deletion of H11 Kinase/Hsp22 Prevents Stress-Induced Activation of STAT3 in the Heart
Cardiac overload increases the expression of the heat shock protein H11 kinase/Hsp22 (Hsp22), which promotes cell survival. An Hsp22 knockout (KO) mouse is comparable to wild type (WT) in sham conditions, but, after transverse aortic constriction (TAC), the KO developed less hypertrophy (myocyte cross-sectional area: 26% versus 70% increase vs shams in KO and WT; P<0.01), more signs of heart failure (lung weight/tibial length: 270% vs 180% increase in KO vs WT; P<0.05), and showed doubled mortality (53% vs 27% in KO vs WT; P<0.01). We tested the hypothesis that Hsp22 participates in activation of stress signaling pathways during overload. Microarrays 3 days after TAC showed that hearts from KO mice fail to activate expression of genes regulated by STAT3, a stress-induced, cytoprotective transcription factor and activator of mitochondrial respiration. Phosphorylation of nuclear STAT3 decreased by 60% (P<0.05) in KO versus WT, and did not increase in response to TAC, as opposed to WT. Mitochondrial translocation of STAT3 and mitochondrial respiration were decreased by 50% in KO versus WT (P<0.05). Reciprocally, a transgenic (TG) model of Hsp22 over-expression showed significant (P<0.05) increase in STAT3 nuclear phosphorylation (5-fold) and mitochondrial translocation (3-fold), and in mitochondrial respiration (30%) versus WT. Hsp22 over-expression in cardiomyocytes dose-dependently increased STAT3 phosphorylation and DNA binding activity by up to 3-fold (P<0.05). Expression of interleukin-6 (IL-6), a secreted cytokine activating STAT3, increased in response to Hsp22 (P<0.05), both in myocytes and in culture medium. DNA binding activity of the transcription factor NF-κB, an activator of the IL-6 gene, increased by 4-fold in response to Hsp22 (P<0.05). NF-κB inhibition by SN50 blocked Hsp22-mediated increase in IL-6 and in STAT3 DNA binding activity. Hsp22 knockdown by siRNA prevented STAT3 phosphorylation in response to IL-6, or in response to interleukin-1β, an NF-κB activator. Therefore, Hsp22 is sufficient and necessary for activation of STAT3 by NF-κB and promotes both nuclear and mitochondrial functions of STAT3. Deletion of Hsp22 in vivo deteriorates the response to overload in terms of ventricular function, heart failure and mortality.
- © 2010 by American Heart Association, Inc.