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J Mol Cell Cardiol. 2013 Sep;62:179-88. doi: 10.1016/j.yjmcc.2013.06.004. Epub 2013 Jun 14.

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice.

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Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.


Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions. However the role of iNKT cells has not been determined in myocardial ischemia/reperfusion (I/R) injury. The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (α-GC), which specifically activates iNKT cells, could affect myocardial I/R injury. I/R or sham operation was performed in male C57BL/6J mice. I/R mice received the injection of either αGC (I/R+αGC, n=48) or vehicle (I/R+vehicle, n=49) 30 min before reperfusion. After 24h, infarct size/area at risk was smaller in I/R+αGC than in I/R+vehicle (37.8 ± 2.7% vs. 47.1 ± 2.5%, P<0.05), with no significant changes in area at risk. The numbers of infiltrating myeloperoxidase- and CD3-positive cells were lower in I/R+αGC. Apoptosis evaluated by TUNEL staining and caspase-3 protein was also attenuated in I/R+αGC. Myocardial gene expression of tumor necrosis factor-α and interleukin (IL)-1β in I/R+αGC was lower to 46% and 80% of that in I/R+vehicle, respectively, whereas IL-10, IL-4, and interferon (IFN)-γ were higher in I/R+αGC than I/R+vehicle by 2.0, 4.1, and 9.6 folds, respectively. The administration of anti-IL-10 receptor antibody into I/R+αGC abolished the protective effects of αGC on I/R injury (infarct size/area at risk: 53.1 ± 5.2% vs. 37.4 ± 3.5%, P<0.05). In contrast, anti-IL-4 and anti-IFN-γ antibodies did not exert such effects. In conclusion, activated iNKT cells by αGC play a protective role against myocardial I/R injury through the enhanced expression of IL-10. Therapies designed to activate iNKT cells might be beneficial to protect the heart from I/R injury.


2,3,5-triphenyltetrazolium chloride; AAR; Cytokines; I/R; IFN-γ; IL; IS; Inflammation; Invariant natural killer T cells; LV; MI; MNCs; MPO; Myocardial ischemia/reperfusion injury; NK; T cell receptor; T(H)1; T(H)2; T-helper type 1; T-helper type 2; TCR; TGF-β; TNF-α; TTC; area at risk; iNKT; infarct size; interferon-γ; interleukin; invariant natural killer T; ischemia/reperfusion; left ventricle; mononuclear cells; myeloperoxidase; myocardial infarction; natural killer; qRT-PCR; quantitative reverse transcriptase-polymerase chain reaction; transforming growth factor-β; tumor necrosis factor-α; α-galactosylceramide; αGC

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