Abstract
Introduction: Cardiac preconditioning against ischemia/reperfusion (I/R) injury can be achieved both acutely-transient ischemia minutes before I/R-and in a delayed fashion-by lipopolysaccharide (LPS) administration hours before. Interestingly, activation of Toll-Like Receptor 4 (TLR4), the dominant transducer of LPS, causes rapid production (within minutes) of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS) as well as inflammatory cytokines such as IL-1β. The purposes of this study were to determine whether activation of TLR4 acutely protects the myocardium from post-ischemic dysfunction and whether IL-1β and/or iNOS are required. Methods: Three mouse strains were used: wild-type, iNOS knockouts and IL-1β knockouts. Hearts in each group were perfused by the Langendorff technique and received either LPS (1μg/cc) or carrier for 30 min followed immediately by 20 min of ischemia and 60 min reperfusion. At the end of reperfusion, recovery of the baseline left ventricular developed pressure (rLVDP) was compared between groups. Tissue IL-1β and nitrate/nitrite levels after I/R were measured by ELISA and the Griess reaction, respectively. To confirm the role of TLR4, paclitaxel (30μM)-a known TLR4 activator-was substituted for LPS and compared to carrier. Results: In the wild-type, both LPS and paclitaxel were protective: LPS failed to protect the iNOS or IL1-β knockout hearts. IL-β and nitrate/nitrite were both elevated following I/R in wild-type; LPS pre-treatment further enhanced these levels. Conclusions: Transient activation of TLR4 by either LPS or paclitaxel in the isolated heart confers functional protection from subsequent I/R injury. The mechanism appears to require both an intact iNOS and IL-1β production and likely involves increased levels of NO and IL-1β.TABLE—ABSTRACT 49TreatmentrLVDPP (by ANOVA)LPS58 ± 2.6%<0.001carrier (perfusate buffer)32 ± 5.3%paclitaxel56 ± 2.4%<0.006carrier (0.1% albumin + DMSO)30 ± 5.7%
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