Background-Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple-protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury. Methods and Results-We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1␤ production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these inflammatory responses and subsequent injuries, including infarct development and myocardial fibrosis and dysfunction, were markedly diminished. Bone marrow transplantation experiments with apoptosis-associated speck-like adaptor protein-deficient mice revealed that inflammasome activation in bone marrow cells and myocardial resident cells such as cardiomyocytes or cardiac fibroblasts plays an important role in myocardial I/R injury. In vitro experiments revealed that hypoxia/reoxygenation stimulated inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, and that hypoxia/reoxygenation-induced activation was mediated through reactive oxygen species production and potassium efflux. Conclusions-Our results demonstrate the molecular basis for the initial inflammatory response after I/R and suggest that the inflammasome is a potential novel therapeutic target for preventing myocardial I/R injury. (Circulation. 2011;123:594-604.)Key Words: cytokine Ⅲ heart Ⅲ hypoxia Ⅲ inflammation Ⅲ leukocyte I ncreasing evidence indicates that inflammation is involved in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. 1 One prominent and early mediator for inflammation in I/R injury is interleukin-1␤ (IL-1␤). 2,3 I/R induces IL-1␤ expression in the heart, and the inhibition of IL-1␤ prevents myocardial injury after I/R, 3 suggesting that the deleterious effects of myocardial I/R are mediated, at least in part, by IL-1␤. In the generation of IL-1␤, pro-IL-1␤, an inactive precursor, undergoes proteolysis by the converting enzyme caspase-1. Caspase-1 is activated within a cytosolic multiprotein complex, the inflammasome. The inflammasome contains cytoplasmic receptors of the NACHT leucine-rich-repeat protein family that are associated with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which in turn recruits and activates caspase-1. 4,5 Increasing evidence indicates that several sterile inflammatory responses triggered by tissue damage are mediated by th...

Danon disease is an X-linked dominant multisystem disorder affecting predominantly cardiac and skeletal muscles.