Inhibition of graft arteriosclerosis development in rat aortas following heme oxygenase-1 gene transfer.
Heme oxygenase 1 (HO-1) is an enzyme which degrades heme into tree end products: biliverdin, free iron and carbon monoxide. This enzyme has recently been shown to have anti-inflammatory and tissue protective effects. HO-1 expression is involved in organ protection in pathological situations, and immunosuppressive treatments resulting in indefinite graft survival without chronic rejection have been associated with HO-1 expression by cells of the vessel wall. The aim of this study was to analyze the effect of specific HO-1 overexpression. We used a recombinant adenovirus coding for human HO-1 cDNA in a rat aorta chronic rejection model, 30 days after transplantation. Control groups included rats non treated or treated with a non-coding adenovirus Addl324. We first demonstrated that AdHO-1 was efficiently expressed in endothelial cells in vitro, and in rat aortas ex vivo after adenovirus gene transfer. We found that intimal thickening in AdHO-1 treated aortas (10.8 +/- 3.8%, n=5) was significantly decreased compared to untreated (21.2 +/- 5.6%, n = 5) or Addl324-treated (21.1 +/- 1.2%, n = 4) aortas. Immunohistology showed that treatment with AdHO-1 resulted in a significant reduction in leukocyte infiltration and a decreasing number of VSMC in the intima, compared to Addl324-treated aortas. However, this effect of HO-1 on chronic rejection did not imply modifications on numbers of apoptotic cells in the graft or of alloantibody levels. We have demonstrated, for the first time, that specific HO-1 overexpression following gene transfer of HO-1 inhibited chronic rejection by reducing leukocyte and VSMC infiltration of the aorta intima.
INSERM U437 and ITERT, Nantes, France.
D
D
Bouche
C
C
Chauveau
J C
JC
Roussel
P
P
Mathieu
C
C
Braudeau
L
L
Tesson
J P
JP
Soulillou
S
S
Iyer
R
R
Buelow
I
I
Anegon
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000517:prevention & control*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006084:Graft Rejection / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D051381:Rats; D011917:Rats, Inbred Lew
D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1