Attenuation of aortic graft arteriosclerosis by systemic administration of Allotrap peptide RDP58.
There remains no treatment for chronic allograft rejection mainly manifested by progressive arteriosclerosis. We investigated the effect of Allotrap peptide RDP58 therapy on arteriosclerosis in an aortic allotransplant model. RDP58 was administered intraperitoneally at 0.1, 0.5, or 2.5 mg/kg, every other day after transplantation. RDP58 therapy markedly inhibited vascular intimal thickening, media necrosis, and adventitial cellular inflammation. The attenuation of arteriosclerosis was associated with the induction of heme oxygenase (HO)-1 expression, inhibition of TNF-alpha production in aortic allografts, as well as decreased specific complement-dependent cytotoxic antibodies in serum. RDP58 inhibited both smooth muscle cell (SMC) proliferation with an 80% inhibition at 100 microM without evidence of cytotoxicity and TNF-induced apoptosis of SMCs in a dose-dependent fashion. These data suggest that the suppressive effect of RDP58 on allograft arteriosclerosis is due to multiple actions of the peptide, including induction of HO-1, inhibition of TNF-alpha, and a direct effect on SMC proliferation.
Li
Wei
W
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, E1540, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, Pennsylvania, USA.
Iyer
Suhasini
S
Lu
Lina
L
Buelow
Roland
R
Fung
John J
JJ
Rao
Abdul S
AS
Woo
Jacky
J
Qian
Shiguang
S
D000818:Animals; D001013:Aorta, Thoracic / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D002455:Cell Division; D002460:Cell Line; D002908:Chronic Disease; D003165:Complement System Proteins / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D001323:Autoantibodies; D008565:Membrane Proteins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C092373:allotrap; D003165:Complement System Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse