The Interaction Between HSP70 and TNF-?? Expression: A Novel Mechanism for Protection of the Myocardium Against Post-Injury Depression

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Abstract
Tumor necrosis factor-α (TNF-α) depresses myocardial contractility, and overexpression of TNF-α in the myocardium contributes to cardiac dysfunction caused by both systemic and local insults. Sepsis, endotoxemia, hemorrhagic shock, and myocardial ischemia-reperfusion all promote cardiac dysfunction in part by a TNF-α-mediated mechanism. Thus, TNF-α represents an appealing therapeutic target for myocardial protection against multiple clinically relevant insults. The inducible 70-kD heat shock protein (Hsp70) is expressed in the myocardium in response to stress and has been linked to enhanced myocardial resistance to depression associated with ischemia-reperfusion or sepsis. The mechanism by which Hsp70 protects cardiac function against a subsequent insult remains obscure. In vitro induction of Hsp70 in monocytes or macrophages inhibits TNF-α production following bacterial lipopolysaccharide stimulation, and in vivo induction of Hsp70 down-regulates tissue TNF-α production following an injurious insult. Understanding of the regulatory role of Hsp70 in the myocardial inflammatory response will provide insights into the mechanism by which Hsp70 preserves cardiac function and may yield therapies for protection of the myocardium against depression associated injurious insults.