CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis.
CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis.
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DOI：
10.1172/jci.insight.97054
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发表时间：
2018-06
期刊：
影响因子：
8
通讯作者：
A. Willeford;T. Suetomi;Audrey C. Nickle;H. Hoffman;S. Miyamoto;Joan Heller Brown
中科院分区：
文献类型：
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作者：
A. Willeford;T. Suetomi;Audrey C. Nickle;H. Hoffman;S. Miyamoto;Joan Heller Brown
炎症伴随心力衰竭，是心脏纤维化的介质。CaMKIIδ在心力衰竭的不良重构和失代偿中起重要作用。我们推测炎症是CaMKIIδ在非缺血性干预中导致不良重构的机制。我们证明，心肌细胞（CKO）中CaMK Ⅱ δ的缺失显著减弱了NF-κB B的活化、炎性趋化因子和细胞因子的表达以及血管紧张素Ⅱ（Ang Ⅱ）输注诱导的巨噬细胞蓄积。炎性小体被Ang II激活，并且这种反应在CKO小鼠中也减弱。这些事件发生在Ang II诱导细胞死亡的任何证据之前。此外，早在输注的第三小时就观察到CaMKII依赖性炎症基因表达和炎性小体引发，此时巨噬细胞募集不明显。抑制炎性小体或单核细胞趋化蛋白1（MCP 1）信号转导减弱了巨噬细胞的积聚，这些干预措施，如心肌细胞CaMKIIδ缺失，减少了对Ang II的纤维化反应。因此，心肌细胞中CaMKIIδ的激活代表了我们认为是启动炎性小体激活的新机制和导致巨噬细胞募集并最终导致纤维化发展的炎性基因程序。
Inflammation accompanies heart failure and is a mediator of cardiac fibrosis. CaMKIIδ plays an essential role in adverse remodeling and decompensation to heart failure. We postulated that inflammation is the mechanism by which CaMKIIδ contributes to adverse remodeling in response to nonischemic interventions. We demonstrate that deletion of CaMKIIδ in the cardiomyocyte (CKO) significantly attenuates activation of NF-κB, expression of inflammatory chemokines and cytokines, and macrophage accumulation induced by angiotensin II (Ang II) infusion. The inflammasome was activated by Ang II, and this response was also diminished in CKO mice. These events occurred prior to any evidence of Ang II-induced cell death. In addition, CaMKII-dependent inflammatory gene expression and inflammasome priming were observed as early as the third hour of infusion, a time point at which macrophage recruitment was not evident. Inhibition of either the inflammasome or monocyte chemoattractant protein 1 (MCP1) signaling attenuated macrophage accumulation, and these interventions, like cardiomyocyte CaMKIIδ deletion, diminished the fibrotic response to Ang II. Thus, activation of CaMKIIδ in the cardiomyocyte represents what we believe to be a novel mechanism for initiating inflammasome activation and an inflammatory gene program that leads to macrophage recruitment and ultimately to development of fibrosis.