PMID- 28526544
OWN - NLM
STAT- MEDLINE
DCOM- 20180425
LR  - 20180425
IS  - 1874-1754 (Electronic)
IS  - 0167-5273 (Linking)
VI  - 243
DP  - 2017 Sep 15
TI  - Interleukin-18 gene deletion protects against sepsis-induced cardiac dysfunction 
      by inhibiting PP2A activity.
PG  - 396-403
LID - S0167-5273(16)32678-X [pii]
LID - 10.1016/j.ijcard.2017.04.082 [doi]
AB  - 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 cardiotoxicity by 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.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Okuhara, Yoshitaka
AU  - Okuhara Y
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Yokoe, Shunichi
AU  - Yokoe S
AD  - Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka, 
      Japan.
FAU - Iwasaku, Toshihiro
AU  - Iwasaku T
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Eguchi, Akiyo
AU  - Eguchi A
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Nishimura, Koichi
AU  - Nishimura K
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Li, Wen
AU  - Li W
AD  - Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 
      Nishinomiya, Japan.
FAU - Oboshi, Makiko
AU  - Oboshi M
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Naito, Yoshiro
AU  - Naito Y
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Mano, Toshiaki
AU  - Mano T
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Asahi, Michio
AU  - Asahi M
AD  - Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka, 
      Japan.
FAU - Okamura, Haruki
AU  - Okamura H
AD  - Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 
      Nishinomiya, Japan.
FAU - Masuyama, Tohru
AU  - Masuyama T
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan.
FAU - Hirotani, Shinichi
AU  - Hirotani S
AD  - Cardiovascular Division, Department of Internal Medicine, Hyogo College of 
      Medicine, Nishinomiya, Japan. Electronic address: hirotani@hyo-med.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20170504
PL  - Netherlands
TA  - Int J Cardiol
JT  - International journal of cardiology
JID - 8200291
RN  - 0 (Interleukin-18)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
CIN - Int J Cardiol. 2018 Mar 1;254:263. PMID: 29150329
CIN - Int J Cardiol. 2018 Sep 1;266:221. PMID: 29887453
MH  - Animals
MH  - Cells, Cultured
MH  - Enzyme Activation/physiology
MH  - *Gene Deletion
MH  - Heart Diseases/genetics/*metabolism/prevention & control
MH  - Interleukin-18/*deficiency/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myocytes, Cardiac/metabolism
MH  - Protein Phosphatase 2/antagonists & inhibitors/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sepsis/genetics/*metabolism/prevention & control
OTO - NOTNLM
OT  - Akt
OT  - IL-18
OT  - PLN
OT  - PP2A
OT  - Sepsis-induced cardiac dysfunction
EDAT- 2017/05/21 06:00
MHDA- 2018/04/26 06:00
CRDT- 2017/05/21 06:00
PHST- 2016/10/07 00:00 [received]
PHST- 2017/02/20 00:00 [revised]
PHST- 2017/04/24 00:00 [accepted]
PHST- 2017/05/21 06:00 [pubmed]
PHST- 2018/04/26 06:00 [medline]
PHST- 2017/05/21 06:00 [entrez]
AID - S0167-5273(16)32678-X [pii]
AID - 10.1016/j.ijcard.2017.04.082 [doi]
PST - ppublish
SO  - Int J Cardiol. 2017 Sep 15;243:396-403. doi: 10.1016/j.ijcard.2017.04.082. Epub 
      2017 May 4.