Gene Transfer of Heme Oxygenase-1 and Carbon Monoxide Delivery Inhibit Chronic Rejection

Abstract

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.

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

“…More recently, gene transfer of HO-1 resulted in a decrease in graft lesions in aortic and heart chronic rejection and liver transplantation models. [10][11][12] Our results extend and confirm a role for HO-1 in prolonging allograft survival in a strong cardiac rejection model. Prolongation of allograft survival following HO-1 gene transfer was not only observed after i.g.…”

“…32,33 Recently, CO has been shown to have antiinflammatory and protective roles in xenograft 34 and allograft rejection. 10,11 Delivery of CO through CO inhalation or methylene chloride administration markedly prolonged cardiac allograft survival in the cardiac transplantation model described in this work (manuscript in preparation).…”

“…Despite the fact that elevated HO-1 expression reduces graft lesions in allogeneic [10][11][12] and xenogeneic 2 models, the mechanisms involved are not completely understood. HO-1 expression could prolong allograft survival by its cellular protective functions, 1,2 such as antiapoptotic 11,20 or anti-inflammatory 2 activities, which result in reduced graft inflammation and leukocyte recruitment in certain models.…”

“…HO-1 expression could prolong allograft survival by its cellular protective functions, 1,2 such as antiapoptotic 11,20 or anti-inflammatory 2 activities, which result in reduced graft inflammation and leukocyte recruitment in certain models. 10,12 Alternatively, HO-1 activity could inhibit the initiation, amplification or effector phases of allogeneic immune responses. The fact that i.g., i.m.…”

“…Unfortunately, metalloporphyrins can also modulate the action of other heme-containing molecules such as NO synthases (NOS) or soluble guanylate cyclases 8,9 and immunomodulatory peptides may have effects on other molecules independent of HO-1. 7 Subsequently, the capacity of HO-1 to prolong graft survival has been demonstrated by specific overexpression of HO-1 by gene transfer in allograft models [10][11][12] and by the use of HO-1-deficient mice in xenograft models. 2 At the present time, little is known about the effect of selective upregulation of HO-1 on acute allograft rejection.…”