ERK5 promotes TLR2-dependent up-regulation of inflammatory mediator expression induces by global myocardial ischemia

Abstract

Global myocardial ischemia and reperfusion [I/R] injury is predominantly associated with heart transplant and coronary artery bypass graft (CABG) surgery. Toll-like receptor-2 (TLR2) is a pivotal pathogen recognition receptor that has a key role in inflammation and injury. The proinflammatory role for ERK5 downstream of TLR2 in global myocardial I/R has not been reported previously. The aim of this study was to investigate to what extent inflammatory stimuli modify the expression by ERK5 of TLR2. Global myocardial I/R was induced in male TLR2+/+ and TLR2−/− mice using heterotopic abdominal heart transplantation model that allows to subject donor hearts to global hypothermic ischemia and blood reperfusion, which very closely stimulates I/R conditions associated with cardiac surgical operations. The results show that inhibition or siRNA knockdown of ERK5 reduces the TLR2-dependent activation of expression of cytokines, attenuated myocardial injury, less oxidative stress and decreased NF-κB activation and indicating that ERK5 promotes cytokine expression downstream of TLR2. We have identified novel aspects of TLR2 signaling in cold myocardial I/R, including that ERK5 activity is required for TLR2 activation.