Retroinfusion of NF Kappa B decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs

• Published in: Gene therapy Vol. 9; no. 8; pp. 518 - 526
• Main Authors: Kupatt, C, Wichels, R, Deiss, M, Molnar, A, Lebherz, C, Raake, P, von Degenfeld, G, Hahnel, D, Boekstegers, P
• Format: Journal Article
• Language: English
• Published: 01.04.2002
• ISSN: 0969-7128
• DOI: 10.1038/sj/gt/3301673

Myocardial reperfusion injury is partially mediated by postischemic inflammation. Beyond acute PMN recruitment, post-ischemic inflammation comprises subacute PMN adhesion, eg via NF Kappa B activation. In a pig model of 60-min LAD occlusion by PTCA ballon inflation and 1 to 7 days of reperfusion, we investigated the impact of targeted NF Kappa B decoy oligonucleotide (ODN) transfection in the area at risk (AAR) on infarct size and regional myocardial function. After 55 min of LAD occlusion, liposomes containing NF Kappa B ODN were selectively retroinfused into the anterior interventricular vein for 5 min. Then, retroinfusion was stopped and reperfusion was initiated. Where indicated, CD18 antibody IB4 was infused systemically at 30 min of ischemia. Methylen blue and tetrazolium-red staining were used for quantification of the infarct size. Subendocardial segment shortening (SES) by sonomicrometric crystals in infarct area and AAR was assessed under pacing (expressed as % of control region). NF Kappa B decoy ODN retroinfusion reduced infarct size (36 plus or minus 4% versus 49 plus or minus 5% in control hearts at day 7), whereas functional reserve of the AAR (SES 73 plus or minus 17% versus 46 plus or minus 18% at 180/min) tended to improve. Similar effects were observed after IB4 infusion (38 plus or minus 5% infarct size, 85 plus or minus 7% SES at 180/min). A combination of NF Kappa B decoy ODN retroinfusion and IB4 infusion further decreased infarct size (26 plus or minus 2%) and improved functional reserve (SES 94 plus or minus 6% at 180/min). We conclude that NF Kappa B decoy ODN transfection by retroinfusion is feasible in pig hearts and provides post-ischemic cardioprotection in addition to CD18 blockade.