PMID- 27288439
OWN - NLM
STAT- MEDLINE
DCOM- 20170626
LR  - 20201230
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 311
IP  - 2
DP  - 2016 Aug 1
TI  - Dysfunction of mitochondria and deformed gap junctions in the heart of 
      IL-18-deficient mice.
PG  - H313-25
LID - 10.1152/ajpheart.00927.2015 [doi]
AB  - Interleukin-18 (IL-18) was discovered as an interferon-gamma-inducing factor and has 
      been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously 
      expressed both in immune/inflammatory cells and in nonimmune cells, and its 
      biological roles have not been sufficiently elucidated. Here, we demonstrate that 
      IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be 
      related to impaired autophagy. In endurance running tests, IL-18KO mice ran 
      significantly shorter distances compared with wild-type (WT) mice. 
      Echocardiographs indicated disability in the systolic and diastolic functions of 
      the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous 
      localization of gap junctions in the lateral membranes of the IL-18KO cardiac 
      myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 
      in the IL-18KO heart. Electron microscopy revealed unusual localization of 
      intercalated disks, swollen or damaged mitochondria, and broad, indistinct 
      Z-lines in the IL-18KO heart. In accordance with the morphological observation, 
      mitochondrial respiratory function, including that of complexes I and IV, was 
      impaired, and production of reactive oxygen species was augmented in IL-18KO 
      hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than 
      in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous 
      IL-18 upregulated LC3-II and increased the number of intact mitochondria with 
      high mitochondrial membrane potential. These results indicated that IL-18 has 
      roles apart from those as a proinflammatory cytokine in cardiac myocytes and 
      suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial 
      function and gap-junction turnover in cardiac myocytes, possibly by upregulating 
      autophagy.
CI  - Copyright (c) 2016 the American Physiological Society.
FAU - Li, Wen
AU  - Li W
AD  - Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 
      Hyogo, Japan;
FAU - Jin, Denan
AU  - Jin D
AD  - Department of Pharmacology, Osaka Medical College, Osaka, Japan;
FAU - Hata, Masaki
AU  - Hata M
AD  - Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 
      Hyogo, Japan;
FAU - Takai, Shinji
AU  - Takai S
AD  - Department of Pharmacology, Osaka Medical College, Osaka, Japan;
FAU - Yamanishi, Kyosuke
AU  - Yamanishi K
AD  - Department of Neuropsychiatry, Hyogo College of Medicine, Hyogo, Japan;
FAU - Shen, Weili
AU  - Shen W
AD  - Shanghai Key Laboratory of Hypertension, Shanghai, China; and.
FAU - El-Darawish, Yosif
AU  - El-Darawish Y
AD  - Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 
      Hyogo, Japan;
FAU - Yamanishi, Hiromichi
AU  - Yamanishi H
AD  - Hirakata General Hospital for Developmental Disorders, Osaka, Japan.
FAU - Okamura, Haruki
AU  - Okamura H
AD  - Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 
      Hyogo, Japan; haruoka@hyo-med.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20160610
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Connexin 43)
RN  - 0 (GJA1 protein, mouse)
RN  - 0 (Interleukin-18)
RN  - 0 (Map1lc3b protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
SB  - IM
CIN - Am J Physiol Heart Circ Physiol. 2016 Aug 1;311(2):H311-2. PMID: 27342879
MH  - Animals
MH  - Autophagy/*genetics
MH  - Blotting, Western
MH  - Cell Membrane/metabolism/ultrastructure
MH  - Cells, Cultured
MH  - Connexin 43/metabolism
MH  - Echocardiography
MH  - Electron Transport Complex I/metabolism
MH  - Electron Transport Complex IV/metabolism
MH  - Gap Junctions/*ultrastructure
MH  - Interleukin-18/*genetics/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Electron
MH  - Microtubule-Associated Proteins/metabolism
MH  - Mitochondria, Heart/*metabolism
MH  - Myocytes, Cardiac/drug effects/*metabolism/ultrastructure
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Physical Endurance
MH  - Reactive Oxygen Species/metabolism
MH  - Systole
MH  - Up-Regulation
OTO - NOTNLM
OT  - IL-18
OT  - cardiac myocytes
OT  - connexin 43
OT  - gap junction
OT  - mitochondrial autophagy
EDAT- 2016/06/12 06:00
MHDA- 2017/06/27 06:00
CRDT- 2016/06/12 06:00
PHST- 2015/12/03 00:00 [received]
PHST- 2016/06/03 00:00 [accepted]
PHST- 2016/06/12 06:00 [entrez]
PHST- 2016/06/12 06:00 [pubmed]
PHST- 2017/06/27 06:00 [medline]
AID - ajpheart.00927.2015 [pii]
AID - 10.1152/ajpheart.00927.2015 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2016 Aug 1;311(2):H313-25. doi: 
      10.1152/ajpheart.00927.2015. Epub 2016 Jun 10.