The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction.
The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction.
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DOI：
10.1371/journal.pone.0176676
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Takahashi M
中科院分区：
文献类型：
--
作者：
Kobayashi M;Usui-Kawanishi F;Karasawa T;Kimura H;Watanabe S;Mise N;Kayama F;Kasahara T;Hasebe N;Takahashi M
强心苷如地高辛是Na+/K+-ATP酶抑制剂，广泛用于治疗慢性心力衰竭和心律失常;然而，最近的流行病学研究表明地高辛治疗与死亡率增加之间存在关系。我们之前的研究表明，核苷酸结合寡聚化结构域样受体家族pyrin domain-containing 3（NLRP 3）炎性体，调节caspase-1依赖性白细胞介素（IL）-1β的释放，介导无菌性心血管炎症。由于Na+/K+-ATP酶参与炎症反应，我们研究了NLRP 3炎性小体在心脏糖苷诱导的心脏炎症和功能障碍的病理生理学中的作用。强心苷哇巴因在用低剂量脂多糖（LPS）致敏的野生型小鼠中诱导心功能障碍和损伤，尽管在单独用哇巴因或LPS治疗的小鼠中没有观察到心功能障碍。哇巴因还诱导小鼠在用LPS致敏时的心脏炎症反应，如巨噬细胞浸润和IL-1β释放。这些心脏表现在IL-1β缺乏的小鼠中均显著减弱。此外，NLRP 3炎性体组分NLRP 3和半胱天冬酶-1的缺乏也减弱了哇巴因诱导的心功能障碍和炎症。体外实验显示哇巴因诱导NLRP 3炎性小体活化以及随后从巨噬细胞释放IL-1β，并且这种活化由K+流出介导。我们的研究结果表明，强心苷通过NLRP 3炎性体促进心脏炎症和功能障碍，并为强心苷不良反应的机制提供了新的见解。
Cardiac glycosides such as digoxin are Na+/K+-ATPase inhibitors that are widely used for the treatment of chronic heart failure and cardiac arrhythmias; however, recent epidemiological studies have suggested a relationship between digoxin treatment and increased mortality. We previously showed that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, which regulate caspase-1-dependent interleukin (IL)-1β release, mediate the sterile cardiovascular inflammation. Because the Na+/K+–ATPase is involved in inflammatory responses, we investigated the role of NLRP3 inflammasomes in the pathophysiology of cardiac glycoside-induced cardiac inflammation and dysfunction. The cardiac glycoside ouabain induced cardiac dysfunction and injury in wild-type mice primed with a low dose of lipopolysaccharide (LPS), although no cardiac dysfunction was observed in mice treated with either ouabain or LPS alone. Ouabain also induced cardiac inflammatory responses, such as macrophage infiltration and IL-1β release, when mice were primed with LPS. These cardiac manifestations were all significantly attenuated in mice deficient in IL-1β. Furthermore, deficiency of NLRP3 inflammasome components, NLRP3 and caspase-1, also attenuated ouabain-induced cardiac dysfunction and inflammation. In vitro experiments revealed that ouabain induced NLRP3 inflammasome activation as well as subsequent IL-1β release from macrophages, and this activation was mediated by K+ efflux. Our findings demonstrate that cardiac glycosides promote cardiac inflammation and dysfunction through NLRP3 inflammasomes and provide new insights into the mechanisms underlying the adverse effects of cardiac glycosides.