© 2004 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Modulating Toll-like receptor mediated signaling by (1
3)-β-D-glucan rapidly induces cardioprotection
aDepartment of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
bModel Animal Research Center, Nanjing University, Nanjing 210093, China
cDepartment of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
* Corresponding author. Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA. Tel.: +1-423-439-6349; fax: +1-423-439-6259. li{at}mail.etsu.edu
Objective: Immune and inflammatory signaling pathways, initiated by the innate response, are involved in myocardial ischemia/reperfusion (I/R) injury. Toll-like receptor (TLR) mediated MyD88-dependent NF
B pathways play a role in the induction of innate immunity. We have reported that glucan phosphate (GP) improved survival in experimental sepsis, which correlated with decreased tissue NFB activation. In the present study, we report that GP rapidly induced cardioprotection against I/R injury in vivo. Methods: Sprague–Dawley rats were pretreated with GP (40 mg/kg, i.p) 1 h before 45 min of ligation of the left anterior descending coronary followed by reperfusion for 4 and 24 h. Infarction size was examined by triphenyltetrazolium chloride (TTC) staining. NFB activation was analyzed by electrophoretic mobility shift assay (EMSA). IB kinase-β (IKKβ), IL-1 receptor-associated kinase (IRAK) and Phosphoinositide 3-kinase (PI3K) activities were determined by kinase assay with appropriate substrates. Association of TLR4 with MyD88 or with PI3K p85 was assessed by immunoprecipitation with anti-TLR4 followed by immunoblotting with anti-MyD88 or anti-p85. Results: GP treatment reduced infarct size by 47% in rat hearts subjected to reperfusion for 4 h and by 50% following reperfusion for 24 h. The same protective effect was observed when GP was administrated 5 min after initiation of ischemia. The mechanisms of GP induced cardioprotection involve decreased association of TLR4 with MyD88, inhibition of I/R induced IRAK and IKKβ activity and decreased NFB activity. In addition, GP increased TLR4 phosphotyrosine, resulting in increasing PI3K/Akt activity in the myocardium, which correlated with decreased cardiac myocyte apoptosis following I/R. Conclusion: The results suggest that activation of the TLR mediated MyD88-dependent NFB signaling pathway may play an important role in myocardial I/R injury, while stimulation of the PI3K/Akt signaling could serve a protective role. The data indicates that GP treatment shifts the TLR mediated activation signal in I/R from a predominantly NFB pathway to a predominant PI3K/Akt signaling pathway.
KEYWORDS Rat; Ischemia; Infarction; Receptors; Signaling transduction
Time for primary review 21 days
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