Rosiglitazone attenuates transplant arteriosclerosis after allogeneic aorta transplantation in rats.
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.
Onuta
Geanina
G
Department of Cell Biology, Section of Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Rienstra
Heleen
H
de Boer
Jan Freark
JF
Boer
Mark Walther
MW
Roks
Anton J M
AJ
Klatter
Flip A
FA
Uges
Donald R A
DR
Navis
Gerjan
G
Rozing
Jan
J
Hillebrands
Jan-Luuk
JL
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
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