Abstract
Extracellular heat shock proteins (eHsps) in the circulation have recently been found to activate both apoptotic and protective signaling in the heart. However, the role of eHsps in doxorubicin (Dox)-induced heart failure has not yet been studied. The objective of present study was to determine how Dox affects circulating eHsp25 in blood plasma and how eHsp25 affects Dox-induced dilated cardiomyopathy. Wild type mice (HSF-1+/+) were pretreated with 100 µl of heterozygous heat shock factor-1 (HSF-1+/-) mice plasma (which contained four-fold higher eHsp25 compared to wild type mice), HSF-1+/+ plasma or saline, before treating with Dox (6 mg/kg). After 4 weeks of this treatment protocol, HSF-1+/- plasma-pretreated mice showed increased eHsp25 in plasma, and improved-cardiac function (%FS: 37.3±2.1 vs. 26.4 ±4.0) and better life span (31±2 vs. 22±3 days) compared to the HSF-1+/+ plasma or saline-pretreated mice. Pre-incubation of isolated adult cardiomyocytes with HSF- 1+/- plasma or recombinant human Hsp27 (rhHsp27)significantly reduced Dox-induced activation of NF-κB and cytokine release, and delayed cardiomyocyte death. Moreover, when cardiomyocytes were incubated with fluorescent-tagged rhHsp27, a saturation in binding was observed, suggesting that eHsp25 can bind to surface receptors. Competitive assays with a toll-like receptor 2 (TLR2) antibody reduced the rhHSP27 binding, indicating that Hsp25 interacts with TLR2. In conclusion, transfusion of Hsp25 enriched blood plasma protected the heart from Dox-induced cardiotoxicity. Hsp25 antagonized Dox binding to the TLR2 receptor on cardiomyocytes.
- Received January 30, 2012.
- Revision received March 20, 2012.
- Accepted March 20, 2012.
- The American Society for Pharmacology and Experimental Therapeutics