Abstract P295: The Inflammasome Is Involved in Myocardial Ischemia-Reperfusion Injury
Background: Accumulating evidence indicates that inflammation is involved in the pathophysiology of myocardial ischemia-reperfusion (I/R) injury. However, the mechanism of I/R-initiated inflammation remains to be determined. The inflammasome is a multiprotein complex consisting of nod-like receptor (NLR), apoptosis-associated speck-like adaptor protein (ASC), and caspase-1, and regulates caspase-1-dependent maturation of IL-1beta and IL-18. In the present study, we investigated the role of inflammasome in myocardial I/R injury.
Methods and Results: Wild-type (WT), ASC−/−, and caspase-1−/− mice were subjected to 30 min LAD ligation, followed by reperfusion. ASC and caspase-1 were expressed at the site of myocardial I/R injury. Deficiency of ASC and caspase-1 reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and subsequent injuries such as infarct development, myocardial fibrosis, and dysfunction in myocardial I/R injury. To determine the contribution of inflammasome in bone marrow cells, we produced bone marrow transplant mice and found that inflammasome activation was critical not only in bone marrow cells but also in myocardial resident cells. Since myocardial damage was observed before the inflammatory cell infiltration after I/R, we hypothesized that myocardial resident cells are responsible for an initial activation of inflammasome. To test this hypothesis, we examined whether hypoxia/reoxygenation (H/R) stimuli could induce inflammasome activation in cardiac fibroblasts and cardiomyocytes in vitro. Interestingly, inflammasome activation was detected only in cardiac fibroblasts, but not in cardiomyocytes, and mediated through reactive oxygen species (ROS) and potassium efflux.
Conclusion: These findings indicate that inflammasome activation in cardiac fibroblasts is essential for inflammation and injury after myocardial I/R, and suggest that the inflammasome is a potential novel therapeutic target for myocardial I/R injury.
- © 2011 by American Heart Association, Inc.