Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca2+/Calmodulin-Dependent Protein Kinase II Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling
Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca2+/Calmodulin-Dependent Protein Kinase II Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling
复制标题
心肌细胞内Ca 2 +/钙调素依赖性蛋白激酶II信号转导介导的压力超负荷引起的炎症和NLRP 3炎症体激活是心脏不良重构的关键
DOI：
10.1161/circulationaha.118.034621
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发表时间：
2018-11-27
期刊：
影响因子：
37.8
通讯作者：
Brown, Joan Heller
中科院分区：
文献类型：
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作者：
Suetomi, Takeshi;Willeford, Andrew;Brown, Joan Heller
背景：炎症与心脏重塑和心力衰竭有关，但在没有细胞死亡的情况下，炎症是如何响应非缺血性干预而启动的尚不清楚。我们测试了心肌细胞（CMs）中Ca2+/钙调素依赖性蛋白激酶II （CaMKII）在压力过载下的激活引发炎症反应，导致不良重塑的假设。方法：CaMKII从CMs（心脏特异性敲除[CKO]）中选择性删除的小鼠和固定的对照组小鼠进行横断主动脉收缩（TAC）。通过定量聚合酶链反应、组织化学和超声心动图心室重构评估cm特异性CaMKII缺失对炎症基因表达、炎症小体激活、巨噬细胞积聚和纤维化的影响。结果：TAC诱导心肌促炎趋化因子和细胞因子mRNA水平在3天内升高，当CM CaMKII被删除时，这些反应明显减弱。此时未见凋亡和坏死细胞死亡。从TAC心脏分离的CMs反映了这些基因表达的强劲增长，而在CKO中明显减弱。通过测量白介素-1和nod样受体含pyrin结构域蛋白3的mRNA水平、caspase-1活性和白介素-18切割，在对照心脏和从这些心脏分离的CMs中，TAC后第3天，nod样受体含pyrin结构域蛋白3炎性体的启动和激活增加。这些反应依赖于CaMKII，并与核因子κ B和活性氧的活化有关。通过阻断单核细胞趋化蛋白-1信号、缺失CM单核细胞趋化蛋白-1或抑制炎性小体激活，在TAC后第7至14天观察到CKO中巨噬细胞的积累减少。这些干预措施也减轻了CKO心脏的纤维化。在TAC后第42天观察到的CKO心室扩张和收缩功能障碍减少。CaMKII、核因子- κ B、炎性体或单核细胞趋化蛋白-1信号在TAC后的前1或2周抑制可减少重塑，但CaMKII在2周后的抑制则没有。结论：CaMKII在压力过载反应中激活可触发炎症基因表达和cm中nod样受体pyrin结构域蛋白3炎性小体的激活。这些反应为巨噬细胞募集、纤维化和心脏心肌功能障碍提供信号。我们的研究表明，靶向由CM CaMKII信号诱导的早期炎症反应对于预防心力衰竭的进展非常重要。
Background: Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to nonischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in cardiomyocytes (CMs) in response to pressure overload elicits inflammatory responses leading to adverse remodeling.Methods: Mice in which CaMKII was selectively deleted from CMs (cardiac-specific knockout [CKO]) and floxed control mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKII deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation, and fibrosis were assessed by quantitative polymerase chain reaction, histochemistry, and ventricular remodeling by echocardiography.Results: TAC induced increases in cardiac mRNA levels for proinflammatory chemokines and cytokines in 3 days, and these responses were significantly blunted when CM CaMKII was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression, which were markedly attenuated in CKO. Priming and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome, assessed by measuring interleukin-1 and NOD-like receptor pyrin domain-containing protein 3 mRNA levels, caspase-1 activity, and interleukin-18 cleavage, were increased at day 3 after TAC in control hearts and in CMs isolated from these hearts. These responses were dependent on CaMKII and associated with activation of Nuclear Factor-kappa B and reactive oxygen species. Accumulation of macrophages observed at days 7 to 14 after TAC was diminished in CKO and, by blocking Monocyte Chemotactic Protein-1 signaling, deletion of CM Monocyte Chemotactic Protein-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 after TAC were diminished in the CKO. Inhibition of CaMKII, Nuclear Factor-kappa B, inflammasome, or Monocyte Chemotactic Protein-1 signaling in the first 1 or 2 weeks after TAC decreased remodeling, but inhibition of CaMKII after 2 weeks did not.Conclusions: Activation of CaMKII in response to pressure overload triggers inflammatory gene expression and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by CM CaMKII signaling to prevent progression to heart failure.