Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion
- 1 June 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 294 (6), H2805-H2813
- https://doi.org/10.1152/ajpheart.00299.2008
Abstract
Previous studies showed that Toll-like receptor 4 (TLR4) modulates the myocardial inflammatory response to ischemia-reperfusion injury, and we recently found that cytokines link TLR4 to postischemic cardiac dysfunction. Although TLR4 can be activated in cultured cells by endogenous agents including heat shock protein 70, how it is activated during myocardial ischemia-reperfusion is unknown. In the present study, we examined 1) whether heat shock cognate protein 70 (HSC70), which is constitutively expressed in the myocardium, is released during ischemia-reperfusion; 2) whether extracellular HSC70 induces the myocardial inflammatory response and modulates cardiac function; and 3) whether HSC70 exerts these effects via TLR4. We subjected isolated mouse hearts to global ischemia-reperfusion via the Langendorff technique. Immunoblotting and immunostaining detected the release of HSC70 from the myocardium during reperfusion. Treatment with an antibody specific to HSC70 suppressed myocardial cytokine expression and improved cardiac functional recovery after ischemia-reperfusion. Recombinant HSC70 induced NF-κB activation and cytokine expression and depressed myocardial contractility in a TLR4-dependent manner. These effects required the substrate-binding domain of HSC70. Fluorescence resonance energy transfer analysis of isolated macrophages demonstrated that extracellular HSC70 interacts with TLR4. Therefore, this study demonstrates for the first time that 1) the myocardium releases HSC70 during ischemia-reperfusion, 2) extracellular HSC70 contributes to the postischemic myocardial inflammatory response and to cardiac dysfunction, 3) HSC70 exerts these effects through a TLR4-dependent mechanism, and 4) the substrate-binding domain of HSC70 is required to induce these effects. Thus extracellular HSC70 plays a critical role in regulating the myocardial innate immune response and cardiac function after ischemia-reperfusion.Keywords
This publication has 36 references indexed in Scilit:
- Cytokines Link Toll-Like Receptor 4 Signaling to Cardiac Dysfunction After Global Myocardial IschemiaThe Annals of Thoracic Surgery, 2008
- Heat Shock Proteins 27, 60, 70, 90α, and 20S Proteasome in On-Pump Versus Off-Pump Coronary Artery Bypass Graft PatientsThe Annals of Thoracic Surgery, 2008
- The interaction between myocardial depressant factors in endotoxemic cardiac dysfunction: Role of TNF-α in TLR4-mediated ICAM-1 expressionCytokine, 2007
- Extracellular heat shock proteins in cell signalingFEBS Letters, 2007
- Enhanced expression of heat shock proteins in gradually dying cells and their release from necrotically dead cellsExperimental Cell Research, 2005
- Release of heat shock proteins (Hsps) and the effects of extracellular Hsps on neural cells and tissuesInternational Journal of Hyperthermia, 2005
- Association of heat shock proteins and neuronal membrane components with lipid rafts from the rat brainJournal of Neuroscience Research, 2005
- Roles of heat-shock proteins in innate and adaptive immunityNature Reviews Immunology, 2002
- Myocardial Heat Shock Proteins during the Development of Heart FailureBiochemical and Biophysical Research Communications, 2001
- High-resolution solution structure of the 18 kDa substrate-binding domain of the mammalian chaperone protein Hsc70 1 1Edited by P. E. WrightJournal of Molecular Biology, 1999