AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts

Abstract

Treating donor hearts with decoy ODNs neutralizing AP-1 or STAT-1 at the time of transplantation prevents upregulation of CD40 expression in the graft coronary arteries and effectively inhibits CAV.

Varicose Remodeling of Veins Is Suppressed by 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Inhibitors

“…Considering arterial diseases, statins have repeatedly been reported to counteract progression of arterial diseases and reduce the 5‐year incidence of major coronary events or stroke,23, 24 effects that may be exerted independently from their HMG‐CoA reductase inhibitory capacity. A pleiotropic effect mediated by this class of drugs is inhibition of the activity of transcription factors such as AP‐1 or nuclear factor‐κB,13 which control expression of genes that have been associated with pathological vascular remodeling processes25, 26, 27 and responses of vascular cells to elevated biomechanical stress 28. Accordingly, atorvastatin and especially rosuvastatin, which is a more potent and water‐soluble inhibitor of HMG‐CoA reductase, inhibited proliferation of AP‐1 activity in stretch‐stimulated venous SMCs as well as expression of its target genes MCP1 and MMP2 in isolated perfused veins exposed to supraphysiological pressure levels.…”

Pre-Transplant Therapy in Experimental Heart Transplantation

“…To investigate this novel therapeutic concept in terms of acute and chronic graft rejection, STAT-1 decoy ODNs were applied in established models of allogeneic cardiac transplantation in rats and mice with or without immunosuppression and in both acute and chronic settings (Holschermann et al, 2006;Stadlbauer et al, 2008;Stojanovic et al, 2009). The exclusive uptake of the decoy ODNs by the donor coronary endothelium could be confirmed by administration of fluorescent dye-labelled nucleic acids.…”

“…CD40, VCAM-1, E-selectin, MCP-1, ICAM-1 and RANTES (Holschermann et al, 2006;Stojanovic et al, 2009) was analyzed. Furthermore, histological parameters of rejection and the profile of infiltrating inflammatory cells were monitored (Holschermann et al, 2006;Stadlbauer et al, 2008;Stojanovic et al, 2009). …”

“…Thus decoy ODNs directed against the transcription factor AP-1 also inhibited endothelial ICAM-1 and VCAM-1 expression and reduced the number of leukocytes, namely T-cells, infiltrating the graft blood vessels, and prolonged survival in acute rejection of cardiac allografts (Holschermann et al, 2006). Analyzing the course of chronic rejection after single application of either a STAT-1 or AP-1 decoy ODN in a rat cardiac transplantation model with immunosuppression revealed that after 100 days allografts treated with either decoy ODN showed a significantly lesser degree of disease and number of occluded vessels, pointing towards a profound inhibition of cardiac allograft vasculopathy (CAV) (Stadlbauer et al, 2008). As putative mechanism of action, it was proposed that the AP-1 decoy ODN primarily attenuated basal endothelial CD40 expression while the STAT-1 decoy ODN suppressed tumour necrosis factor-/IFN--stimulated expression of CD40 in the rat native endothelial cells (Stadlbauer et al, 2008).…”

Delivery of Gene and Cellular Therapies for Heart Disease

“…From a historical viewpoint, it is notable that this technique is found in earliest gene therapy clinical studies [17]. Ex vivo modification of adult-derived progenitor cells is plausible [18], as is ex vivo to the donor heart pretransplant [19][20][21][22], although a need exists to overcome issues related to vector-mediated responses in immunosuppressed states.…”