VEGF165 transfection decreases postischemic NF-kappa B-dependent myocardial reperfusion injury in vivo: role of eNOS phosphorylation.
Endothelial nitric oxide synthase (eNOS) phosphorylation increases nitric oxide formation, for example, after VEGF stimulation. We investigated whether nitric oxide formed after overexpression of VEGF or of phosphomimetic eNOS (S1177D) affects PMN-induced myocardial detriment after ischemia and reperfusion. Pigs (n=8 per group) were subjected to percutaneous liposome-based gene transfer by retroinfusion of the anterior interventricular vein 48 h before LAD occlusion (60 min) and reperfusion (24 h). Thereafter, regional myocardial function was assessed as subendocardial segment shortening (SES), and infarct size was determined. Tissue from the infarct region, the noninfarcted area at risk, and a control region was analyzed for NF-kappaB activation (EMSA), tumor necrosis factor (TNF)-alpha, and E-selectin mRNA and infiltration of polymorphonuclear neutrophils (PMN). L-NAME was applied in one group of VEGF-transfected animals. NF-kappaB activition, PMN infiltration in the infarct region, and AAR were reduced after transfection of VEGF or eNOS S1177D, but not after VEGF+L-NAME coapplication. Infarct size decreased, whereas SES improved after either VEGF or eNOS S1177D transfection, an effect inhibited by L-NAME coapplication. Retroinfusion of liposomal VEGF cDNA reduces NF-kappaB-dependent postischemic inflammation and subsequent myocardial reperfusion injury, an effect mediated at least in part by enhanced eNOS phosphorylation.
Kupatt
Christian
C
Internal Medicine I, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany. c.kupatt@lrz.uni-muenchen.de
Hinkel
Rabea
R
Vachenauer
Robert
R
Horstkotte
Jan
J
Raake
Philip
P
Sandner
Torleif
T
Kreuzpointner
Robert
R
Müller
Fabian
F
Dimmeler
Stefanie
S
Feron
Olivier
O
Boekstegers
Peter
P
D000818:Animals; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008081:Liposomes; D008222:Lymphokines / Q000235:genetics* / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016328:NF-kappa B / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D013552:Swine; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008081:Liposomes; D008222:Lymphokines; D016328:NF-kappa B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester