| RRC ID |
65124
|
| 著者 |
Kobayashi M, Usui-Kawanishi F, Karasawa T, Kimura H, Watanabe S, Mise N, Kayama F, Kasahara T, Hasebe N, Takahashi M.
|
| タイトル |
The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction.
|
| ジャーナル |
PLoS One
|
| Abstract |
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.
|
| 巻・号 |
12(5)
|
| ページ |
e0176676
|
| 公開日 |
2017-1-1
|
| DOI |
10.1371/journal.pone.0176676
|
| PII |
PONE-D-17-06814
|
| PMID |
28493895
|
| PMC |
PMC5426608
|
| MeSH |
Animals
Biological Transport / drug effects
Caspase 1 / metabolism
Inflammasomes / metabolism*
Inflammation / pathology*
Inflammation / physiopathology*
Interleukin-1beta / deficiency
Interleukin-1beta / metabolism
Macrophages / drug effects
Macrophages / metabolism
Macrophages / pathology
Mice, Inbred C57BL
Myocardium / enzymology
Myocardium / metabolism*
Myocardium / pathology*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
Ouabain / adverse effects*
Potassium / metabolism
|
| IF |
2.74
|
| リソース情報 |
| ヒト・動物細胞 |
J774.1(RCB0434) |
