N,N-dimethylsphingosine attenuates myocardial ischemia–reperfusion injury by recruiting regulatory T cells through PI3K/Akt pathway in mice

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• 作者：Jun Fang ; Fudong Hu ; Dan Ke ; Yuanming Yan ; Zhenmei Liao…
• 关键词：N ; N ; dimethylsphingosine ; Myocardial ischemia ; Reperfusion injury ; Regulatory T cells ; Phosphatidylinositol 3 ; kinase
• 刊名：Basic Research in Cardiology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：111
• 期：3
• 全文大小：7,913 KB
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• 作者单位：Jun Fang (1)
  Fudong Hu (1)
  Dan Ke (1) (2)
  Yuanming Yan (1)
  Zhenmei Liao (1)
  Xun Yuan (1)
  Lingzhen Wu (1)
  Qiong Jiang (1)
  Lianglong Chen (1)
  
  1. Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Heart Disease, 29 Xin-Quan Road, Fuzhou, 350001, Fujian, People’s Republic of China
  2. Department of Cardiology, Fujian Provincial Corps Hospital, Chinese People’s Armed Police Forces, Fuzhou, People’s Republic of China
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Cardiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1435-1803

文摘

N,N-dimethylsphingosine (DMS) has been documented to be in vitro protective against myocardial ischemia–reperfusion injury (IRI) and can recruit CD4+CD25+Foxp3+ regulatory T cells (Tregs), which may participate in the cardioprotection. We hypothesized that when in vivo applied after a myocardial ischemia, DMS may be cardioprotective by recruiting Tregs. Myocardial IRI was induced in C57BL/6 mice by occluding the left main coronary arteries followed by relaxation, and DMS (0.43 mg/kg) was intravenously injected 5 min after the onset of ischemia. We found that in wild-type (WT) mice, compared with the ischemia–reperfusion group, DMS reduced the infarct size (47.1 ± 8.9 vs. 33.1 ± 3.4 %, p < 0.01), and neutrophil infiltration at 24 h reperfusion (R) evaluated by TTC and immunohistochemical staining, respectively, and increased the aggregation of Tregs [(6 ± 1)/mm2 vs. (30 ± 4)/mm2, p < 0.01], peaking at 1 h R by immunofluorescence staining, with reduced gene expression of inflammatory factors at 4 h R in the reperfused myocardium by real-time PCR. This protection was abolished by phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor or Tregs-depleting antibody. Relative to WT mice, the cardioprotection conferred by T cell- and B cell- deficient Rag2 knockout (KO) mice was not strengthened by DMS or by DMS and the adoptive transfer of Tregs from WT mice, but was abolished by DMS and WT non-Tregs and was recaptured by the cotransfer with WT Tregs but not with Akt1+/− mice-derived Tregs. In conclusion, applied at an early stage of ischemia, DMS may be in vivo protective against myocardial IRI by recruiting Tregs via PI3K/Akt pathway.