title: Simvastatin combined with aspirin increases the survival time of heart allograft by activating CD4(+)CD25(+) Treg cells and enhancing vascular endothelial cell protection.
abstract: OBJECTIVE
  The objective was to investigate whether the combination of simvastatin and aspirin treatment prolongs the survival time of the heart allograft in rat and its underlying mechanism.
  
  
  METHODS
  Heterotopic heart transplantation was performed using Wistar rats as donors and Sprague-Dawley (SD) rats as recipients. The SD rats were randomly divided into five groups (n=20/group): sham, HT (heart transplantation), HT+simvastatin (HT+S), HT+aspirin (HT+A), and HT+aspirin+simvastatin (HT+A+S). After transplantation, at 3, 7, 10, 15, 20, 30, and 40 days, the endothelial nitric oxide synthase (eNOS) expression was assessed by immunohistological staining; nitric oxide (NO) levels were analyzed by Griess assay; the activation of CD4(+)CD25(+) T regulatory lymphocytes (Tregs) was analyzed by flow cytometry; and pathological changes in the graft heart were determined by histology.
  
  
  RESULTS
  Combined treatment of hearts with simvastatin and aspirin significantly prolonged the mean survival time of heart allografts [8 ± 1.2 days (n=18), 20 ± 3.4 days (n=19), 21 ± 2.8 days (n=19), and 39 ± 5.3 days (n=19) for HT, HT+S, HT+A, and HT+A+S group, respectively; HT vs. HT+A+S, P<.001; HT vs. HT+S or HT+A, P<.05]. In addition,
  
  
  CONCLUSIONS
  Simvastatin given in combination with aspirin delayed the development of pathological changes in the myocardium, reduced vascular damage and prolonged the survival time of cardiac allograft. The underlying mechanism is linked with CD4(+)CD25(+)-Treg-cell-induced immune tolerance and enhanced vascular endothelial cell protection.
authors.affiliation: Department of Cardiovascular Surgery, Lanzhou university second hospital, Gansu, 730030, China; Department of Cardiothoracic Vascular Surgery, People's Hospital of San Ya City, Hai Nan, 572000, China. Electronic address: zsjg2009@foxmail.com.
authors.forename: Jinguo
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Cardiovascular Surgery, Lanzhou university second hospital, Gansu, 730030, China. Electronic address: bingrengao@sina.com.
authors.forename: Bingren
authors.initials: B
authors.lastname: Gao
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019821:Simvastatin; D001241:Aspirin
keywords: CD(4)(+)CD(25)(+) Treg; Heart transplantation; Vascular endothelial cell