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.
Chauveau
Christine
C
Institut National de la Santé Et de la Recherche Médicale U437, Institut de Transplantation et de Recherche en Transplantation and CHU de Nantes, France.
Bouchet
Delphine
D
Roussel
Jean-Christian
JC
Mathieu
Patrick
P
Braudeau
Cécile
C
Renaudin
Karine
K
Tesson
Laurent
L
Soulillou
Jean-Paul
JP
Iyer
Suhasini
S
Buelow
Roland
R
Anegon
Ignacio
I
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