Abstract 1055: The 70 kDa Heat Shock Cognate Protein Plays A Novel Role In Myocardial Chemokine Expression And Cardiac Dysfunction Following Ischemia And Reperfusion Injury

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Myocardial ischemia and reperfusion (I/R) causes the release of cellular proteins including heat shock proteins (HSPs). The inducible HSP70 induces cytokine production in monocytes and dendritic cells through Toll-like receptor 4 (TLR4) signaling. In evaluation of the role of HSPs in myocardial inflammatory response in a mouse heart global I/R model, we found that the 70 kDa heat shock cognate protein (HSC70), but not HSP70, was released into the extracellular space and the coronary effluent during I/R. These observations prompted us to hypothesize that HSC70 plays a novel role in postischemic myocardial inflammatory response and cardiac dysfunction. Methods: We subjected mouse hearts to global I/R (20 min/60 min) or perfusion using the Langendorff method. We examined: the effect of HSC70 antibody on myocardial chemokine expression and cardiac functional recovery following I/R, the effect of recombinant HSC70 on myocardial chemokine expression and cardiac function and the role of TLR4 and the HSC70 substrate-binding domain in the effect of HSC70 on the heart. Results: In comparison with non-immune IgG, anti-HSC70 reduced myocardial expression of KC and MCP-1 mRNAs and proteins following I/R. Moreover, treatment with anti-HSC70 improved postischemic cardiac functional recovery (66±5.4% of baseline vs. 28±5.1% of baseline in hearts treated with non-immune IgG, p<0.01). Recombinant HSC70 induced myocardial expression of KC and MCP-1 mRNAs and proteins and caused cardiac dysfunction (72±2.6% of baseline vs. 98±3.9% of baseline in perfusion controls, p<0.001) in hearts with competent TLR4 (C3H/HeN). Interestingly, these effects of HSC70 were abrogated in hearts with defective TLR4 (C3H/HeJ). The potency of HSC70 was completely lost in the absence of its substrate-binding domain. Conclusions: Taken together, our studies demonstrate, for the first time, that HSC70 plays an important role in the induction of myocardial chemokines and cardiac dysfunction during I/R. The effect of HSC70 is dependent on TLR4 and requires the presence of the substrate-binding domain. The results suggest that the release of HSC70 into the extracellular space elicits an inflammatory response and causes mechanic dysfunction in the heart.