title: Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury.
abstract: 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-1β 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.
authors.affiliation: Division of Bioimaging Sciences, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan. masafumi2@jichi.ac.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takeki
authors.initials: T
authors.lastname: Hata
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kashima
authors.forename: Fumitake
authors.initials: F
authors.lastname: Usui
authors.forename: Hajime
authors.initials: H
authors.lastname: Morimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Izawa
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Junya
authors.initials: J
authors.lastname: Masumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Koyama
authors.forename: Minoru
authors.initials: M
authors.lastname: Hongo
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Jun
authors.initials: J
authors.lastname: Nakayama
authors.forename: Junji
authors.initials: J
authors.lastname: Sagara
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Uichi
authors.initials: U
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D020170:Caspase 1; D011188:Potassium