title: Rosiglitazone attenuates transplant arteriosclerosis after allogeneic aorta transplantation in rats.
abstract: BACKGROUND
  Transplant arteriosclerosis is a leading cause of chronic transplant dysfunction and is characterized by occlusive neointima formation in intragraft arteries. Development of transplant arteriosclerosis is refractory to conventional immunosuppressive drugs and adequate therapy is not available. In this study, we determined the efficacy of the synthetic peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone to attenuate the development of transplant arteriosclerosis in rat aortic allografts.
  
  
  METHODS
  Lewis aortic allografts were transplanted into Brown Norway recipient rats. Recipient rats received either approximately 5 mg rosiglitazone/day (starting 1 week before transplantation until the end of the experiment) or were left untreated. Transplant arteriosclerosis was quantified using morphometric analysis. Alloreactivity was measured in vitro using mixed lymphocyte reactions. Regulatory T cell frequency and function were analyzed using flow cytometry and in vitro suppression assays, respectively. Intragraft gene expression was analyzed using real-time polymerase chain reaction. Finally, medial and neointimal vascular smooth muscle cell proliferation was analyzed in vitro.
  
  
  RESULTS
  Rosiglitazone significantly reduced transplant arteriosclerosis development 8 weeks after transplantation (P<0.01 vs. nontreated). Rosiglitazone reduced T cell alloreactivity which was not mediated through modulation of CD4+CD25+FoxP3+ regulatory T cells. Reduced development of transplant arteriosclerosis coincided with reduced intragraft expression of stromal-derived factor-1alpha and platelet-derived growth factor receptor-beta. Finally, rosiglitazone reduced growth-factor-driven proliferation of both medial and neointimal vascular smooth muscle cells in vitro, which was not mediated through PPARgamma.
  
  
  CONCLUSIONS
  PPARgamma agonists may offer a new therapeutic strategy in clinical transplantation to attenuate the development of transplant arteriosclerosis and thereby chronic transplant dysfunction.
authors: Department of Cell Biology, Section of Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Geanina
authors: G
authors: Onuta
authors: Heleen
authors: H
authors: Rienstra
authors: Jan Freark
authors: JF
authors: de Boer
authors: Mark Walther
authors: MW
authors: Boer
authors: Anton J M
authors: AJ
authors: Roks
authors: Flip A
authors: FA
authors: Klatter
authors: Donald R A
authors: DR
authors: Uges
authors: Gerjan
authors: G
authors: Navis
authors: Jan
authors: J
authors: Rozing
authors: Jan-Luuk
authors: JL
authors: Hillebrands
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D000077154:Rosiglitazone; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014181:Transplantation Immunology / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D020797:Receptor, Platelet-Derived Growth Factor beta