title: N,N-dimethylsphingosine attenuates myocardial ischemia-reperfusion injury by recruiting regulatory T cells through PI3K/Akt pathway in mice.
abstract: 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)/mm(2) vs. (30 ± 4)/mm(2), 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.
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: 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.
authors.forename: Fudong
authors.initials: F
authors.lastname: Hu
authors.affiliation: 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.|Department of Cardiology, Fujian Provincial Corps Hospital, Chinese People's Armed Police Forces, Fuzhou, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ke
authors.affiliation: 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.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Zhenmei
authors.initials: Z
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Xun
authors.initials: X
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Lingzhen
authors.initials: L
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: 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. lianglongchenxh@126.com.
authors.forename: Lianglong
authors.initials: L
authors.lastname: Chen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D002316:Cardiotonic Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C061800:N,N-dimethylsphingosine; D013110:Sphingosine
keywords: Myocardial ischemia; N,N-dimethylsphingosine; Phosphatidylinositol 3-kinase; Regulatory T cells; Reperfusion injury