Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury
Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury
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DOI：
10.1161/circulationaha.110.982777
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发表时间：
2011-02-15
期刊：
影响因子：
37.8
通讯作者：
Ikeda, Uichi
中科院分区：
文献类型：
--
作者：
Kawaguchi, Masanori;Takahashi, Masafumi;Ikeda, Uichi
背景-炎症在心肌缺血/再灌注（I/R）损伤的病理生理学中起关键作用;然而，心肌I/R诱导炎症的机制尚不清楚。最近的证据表明，由组织损伤引发的无菌炎症反应是通过称为炎性体的多蛋白复合物介导的。因此，我们假设，炎症小体是一个初始传感器的危险信号（S）在心肌I/R injuries.Methods和Results-We证明，炎症小体激活心脏成纤维细胞，但不是在心肌细胞，是至关重要的参与心肌I/R损伤后的初始炎症反应。我们发现炎性小体由I/R形成，并且其随后的炎性小体激活导致白细胞介素-1 β的产生，从而导致炎症反应，例如心脏中的炎性细胞浸润和细胞因子表达。在缺乏糖尿病相关斑点样衔接蛋白和半胱天冬酶-1的小鼠中，这些炎症反应和随后的损伤，包括梗死发展和心肌纤维化和功能障碍，显着减少。骨髓移植实验中与糖尿病相关的斑点样衔接蛋白缺陷小鼠显示，在骨髓细胞和心肌驻留细胞，如心肌细胞或心脏成纤维细胞的炎性小体活化在心肌I/R损伤中起重要作用。体外实验表明，缺氧/复氧刺激炎性小体激活心脏成纤维细胞，但不是在心肌细胞，缺氧/复氧诱导的激活介导的活性氧的产生和钾efflux. Conclusions，我们的研究结果表明，I/R后的初始炎症反应的分子基础，并建议炎性小体是一个潜在的新的治疗靶点，用于预防心肌I/R损伤。（循环。2011;123：594-604.）
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 beta 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.)