Abstract P131: Cardiac Toll-like Receptor 4 (tlr4) is Protective Against Ischemia-reperfusion Injury in Isolated Perfused Hearts
Introduction: The innate immune signaling TLR4 is critical for host defense against microbial infection. Recent studies have suggested that TLR4 signaling may also play an important role in modulating cell survival and in certain non-infectious tissue injury. TLR4 activation stimulates a survival signaling in isolated cardiomyocytes and protects the heart against ischemia-reperfusion (I/R) injury in vivo and in isolated hearts. However, in the absence of systemic TLR4 activation, loss-of-function studies indicate that systemic TLR4-deficiency leads to a decrease in myocardial inflammation and infarction (MI) following I/R and thus, suggest that TLR4 may contribute to the pathogenesis of I/R injury. We hypothesize that circulatory TLR4 contributes to ischemic myocardial infarction by mediating inflammatory injury during I/R and that cardiac TLR4 is protective. To test the hypotheses, the current study examined the impact of TLR4 deficiency on MI size and cardiac function in isolated hearts, a system devoid of circulatory blood components.
Methods: The hearts isolated from wild-type (WT, C57BL/10ScSn) and TLR4−/− (C57BL/10ScCr) mice were retrograde-perfused through aorta. After 20 min of perfusion, the hearts were subjected to 20 min of global ischemia and 40 min of reperfusion. Post-ischemic left ventricular (LV) function as well as myocardial infarct sizes were examined.
Results: The LV function of the isolated hearts was significantly decreased from the baseline. In WT hearts, the rate-pressure product (RPP) was decreased by 55% (26530 ± 2105 at baseline vs.12002 ± 921, p < 0.01, n = 9), dP/dtmax and dP/dtmin decreased by 45% and 49%, respectively (2240 ± 120 at baseline vs. 1223 ± 79 and 1887 ± 100 at baseline vs. 959 ± 56, respectively). However, in the hearts deficient for TLR4, the LV function was much worse than the WT controls following I/R. RPP was 7125 ± 505 (59% of WT, p < 0.001, n = 9), dP/dtmax 758 ± 70 (62% of WT, p < 0.01, n = 9), and dP/dtmin 588 ± 26 (61% of WT, p < 0.001, n = 9). In consistent with the LV function measurement, the TLR4−/− hearts had much larger infarct sizes compared to the WT hearts following I/R (64 ± 5% vs. 28 ± 2%, N = 9, p < 0.001).
Conclusions: These results suggest that cardiac TLR-4 confers a protective benefit during I/R in the isolated hearts.