Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection.
The hallmark of chronic rejection is the occlusion of the artery lumen by intima hyperplasia as a consequence of leukocyte infiltration and vascular smooth muscle cell (VSMC) migration and proliferation. Heme oxygenase-1 (HO-1) is a tissue protective molecule which degrades heme into carbon monoxide (CO), free iron and biliverdin. We analyzed the effects of HO-1 gene transfer into the vessel wall using an adenoviral vector (AdHO-1) and of CO delivery in a model of chronic allogeneic aorta rejection in rats. Carbon monoxide treatment was achieved by a new pharmacological approach in transplantation using methylene chloride (MC), which releases CO after degradation. AdHO-1-mediated gene transfer into aorta endothelial cells (ECs) or CO delivery resulted in a significant reduction in intimal thickness compared to untreated or noncoding adenovirus-treated controls. Aortas transduced with AdHO-1 or treated with CO showed a reduction in the number of leukocytes as well as in the expression of adhesion molecules, costimulatory molecules and cytokines, with the gene transfer treatment displaying a more pronounced effect than the CO treatment. Conversely, CO inhibited VSMC accumulation in the intima more efficiently than AdHO-1 treatment. Gene transfer of HO-1 and pharmacological manipulation of CO are novel approaches to the analysis and treatment of chronic rejection.
Institut National de la Santé Et de la Recherche Médicale U437, Institut de Transplantation et de Recherche en Transplantation and CHU de Nantes, France.
Christine
C
Chauveau
Delphine
D
Bouchet
Jean-Christian
JC
Roussel
Patrick
P
Mathieu
Cécile
C
Braudeau
Karine
K
Renaudin
Laurent
L
Tesson
Jean-Paul
JP
Soulillou
Suhasini
S
Iyer
Roland
R
Buelow
Ignacio
I
Anegon
D000818:Animals; D019556:COS Cells / Q000637:transplantation; D002248:Carbon Monoxide / Q000627:therapeutic use*; D002263:Carboxyhemoglobin / Q000493:pharmacokinetics; D002522:Chlorocebus aethiops; D002908:Chronic Disease; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1