Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury
In: Circulation, Jg. 123 (2011-02-15), S. 594-604
Online
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Zugriff:
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.
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Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury
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Autor/in / Beteiligte Person: | Izawa, Atsushi ; Hata, Takeki ; Usui, Fumitake ; Morimoto, Hajime ; Kashima, Yuichiro ; Takahashi, Masafumi ; Taniguchi, Shun'ichiro ; Kawaguchi, Masanori ; Nakayama, Jun ; Hongo, Minoru ; Ikeda, Uichi ; Koyama, Jun ; Noda, Tetsuo ; Masumoto, Junya ; Sagara, Junji ; Takahashi, Yasuko |
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Zeitschrift: | Circulation, Jg. 123 (2011-02-15), S. 594-604 |
Veröffentlichung: | Ovid Technologies (Wolters Kluwer Health), 2011 |
Medientyp: | unknown |
ISSN: | 1524-4539 (print) ; 0009-7322 (print) |
DOI: | 10.1161/circulationaha.110.982777 |
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