Retroinfusion of NFkappaB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs.
Myocardial reperfusion injury is partially mediated by postischemic inflammation. Beyond acute PMN recruitment, postischemic inflammation comprises subacute PMN adhesion, eg via NFkappaB 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 NFkappaB 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 NFkappaB 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). NFkappaB decoy ODN retroinfusion reduced infarct size (36 +/- 4% versus 49 +/- 5% in control hearts at day 7), whereas functional reserve of the AAR (SES 73 +/- 17% versus 46 +/- 18% at 180/min) tended to improve. Similar effects were observed after IB4 infusion (38 +/- 5% infarct size, 85 +/- 7% SES at 180/min). A combination of NFkappaB decoy ODN retroinfusion and IB4 infusion further decreased infarct size (26 +/- 2%) and improved functional reserve (SES 94 +/- 6% at 180/min). We conclude that NFkappaB decoy ODN transfection by retroinfusion is feasible in pig hearts and provides postischemic cardioprotection in addition to CD18 blockade.
Kupatt
C
C
Internal Medicine I, Klinikum Grosshadern, Munich, Germany.
Wichels
R
R
Deiss
M
M
Molnar
A
A
Lebherz
C
C
Raake
P
P
von Degenfeld
G
G
Hahnel
D
D
Boekstegers
P
P
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D018821:CD18 Antigens / Q000276:immunology; D003331:Coronary Vessels; D004730:Endothelium, Vascular / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D008081:Liposomes; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics*; D009841:Oligonucleotides / Q000008:administration & dosage*; D051381:Rats; D013552:Swine; D014162:Transfection / Q000379:methods*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D008081:Liposomes; D016328:NF-kappa B; D009841:Oligonucleotides