Production of proinflammatory
cytokines contributes to cardiac dysfunction during
ischemia-reperfusion. The principal mechanism responsible for the induction of this innate stress response during periods of
myocardial ischemia-reperfusion remains unknown.
Toll-like receptor 2 (TLR2) is a highly conserved
pattern recognition receptor that has been implicated in the innate immune response to a variety of pathogens. However, TLR2 may also mediate
inflammation in response to noninfectious injury. We therefore hypothesized that TLR2 is essential for modulating myocardial
inflammation and left ventricular (LV) function during
ischemia-reperfusion injury. Susceptibility to
myocardial ischemia-
reperfusion injury following
ischemia-reperfusion was determined in Langendorff-perfused hearts isolated from wild-type mice and mice deficient in TLR2 (TLR2D) and Toll
interleukin receptor domain-containing adaptor
protein. After
ischemia-reperfusion, contractile performance was significantly impaired in hearts from wild-type mice as demonstrated by a lower recovery of LV developed pressure relative to TLR2D hearts.
Creatinine kinase levels were similar in both groups after reperfusion. Contractile dysfunction in wild-type hearts was associated with elevated cardiac levels of TNF and IL-1beta.
Ischemia-reperfusion-induced
LV dysfunction was reversed by treatment with the recombinant TNF blocking
protein etanercept. These studies show for the first time that TLR2 signaling importantly contributes to the
LV dysfunction that occurs following
ischemia-reperfusion. Thus disruption of TLR2-mediated signaling may be helpful to induce immediate or delayed myocardial protection from
ischemia-reperfusion injury.