教員業績データベース |
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論文種別 | 原著 |
言語種別 | 英語 |
査読の有無 | 査読あり |
表題 | Interleukin-18 gene deletion protects against sepsis-induced cardiac dysfunction by inhibiting PP2A activity. |
掲載誌名 | 正式名:International journal of cardiology 略 称:Int J Cardiol ISSNコード:1874-1754(Electronic)0167-5273(Linking) |
掲載区分 | 国外 |
巻・号・頁 | 243,pp.396-403 |
著者・共著者 | Okuhara Yoshitaka, Yokoe Shunichi, Iwasaku Toshihiro, Eguchi Akiyo, Nishimura Koichi, Li Wen, Oboshi Makiko, Naito Yoshiro, Mano Toshiaki, Asahi Michio, Okamura Haruki, Masuyama Tohru, Hirotani Shinichi |
発行年月 | 2017/09 |
概要 | BACKGROUND:Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicityby LPS.METHODS AND RESULTS:Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS. Serial echocardiography showed better systolic pump function and less left ventricular (LV) dilatation in LPS-treated IL-18 KO mice compared with those in LPS-treated WT mice. LPS treatment significantly decreased the levels of phospholamban (PLN) and Akt phosphorylation in WT mice compared with those in saline-treated WT mice, while the LPS-induced decrease in the phosphorylation levels was attenuated in IL-18 KO mice compared with that in WT mice. IL-18 gene deletion also attenuated an LPS-induced increase of type 2 protein phosphatase 2A (PP2A) activity, a molecule that dephosphorylates PLN and Akt. There was no difference in type 1 protein phosphatase (PP1) activity. To address whether IL-18 affects PLN and Akt phosphorylation via PP2A activation in cardiomyocytes, rat neonatal cardiac myocytes were cultured and stimulated using 100ng/ml of recombinant rat IL-18. Exogenous IL-18 decreased the level of PLN and Akt phosphorylation in cardiomyocytes. PP2A activity but not PP1 activity was increased by IL-18 stimulation in cardiomyocytes.CONCLUSIONS:IL-18 plays a pivotal role in advancing sepsis-induced cardiac dysfunction, and the mechanisms underlying IL-18-mediated cardiotoxicity potentially involve the regulation of PLN and Akt phosphorylation through PP2A activity. |
DOI | 10.1016/j.ijcard.2017.04.082 |
PMID | 28526544 |