Cardioselective nitric oxide synthase 3 gene transfer protects against myocardial reperfusion injury.
Nitric oxide modulates the severity of myocardial ischemia-reperfusion (I/R) injury. We investigated whether cardioselective nitric oxide synthase 3 (NOS3) gene transfer could confer myocardial protection against I/R injury in pigs and examined potential molecular mechanisms. I/R injury was induced by balloon occlusion of the left anterior descending artery for 45 min followed by 4 or 72 h reperfusion. Hemodynamic and pathological changes were measured in pigs in the absence (n = 11) or presence of prior intracoronary retroinfusion of human NOS3 (AdNOS3, 5 x 10(10) PFU, n = 13) or control vector (AdRR5, 5 x 10(10) PFU, n = 11). Retrograde NOS3 gene transfer selectively increased NOS3 expression and NO bioavailability in the area at risk (AAR) without changing endogenous NOS isoform expression. At 4 h R, LV systolic (dP/dt(max)) and diastolic (dP/dt(min)) function was better preserved in AdNOS3- than in AdRR5-injected pigs (2,539 +/- 165 vs. 1,829 +/- 156 mmHg/s, and -2,781 +/- 340 vs. -2,062 +/- 292 mmHg/s, respectively, P < 0.05 for both). Myocardial infarct size (% AAR) was significantly smaller in AdNOS3 than in control and AdRR5 and associated with a significantly greater reduction in cardiac myeloperoxidase activity, a marker of neutrophil infiltration. The latter effects were sustained at 72 h R in a subset of pigs (n = 7). In the AAR, intercellular endothelial adhesion molecule-1 expression and cardiomyocyte apoptosis were significantly lower in AdNOS3. In conclusion, single myocardial NOS3 retroinfusion attenuates I/R injury, and causes a sustained reduction in myocardial infarct size and inflammatory cell infiltration. Gene-based strategies to increase NO bioavailability may have therapeutic potential in myocardial I/R.
Szelid
Zsolt
Z
Vesalius Research Center, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
Pokreisz
Peter
P
Liu
Xiaoshun
X
Vermeersch
Pieter
P
Marsboom
Glenn
G
Gillijns
Hilde
H
Pellens
Marijke
M
Verbeken
Erik
E
Van de Werf
Frans
F
Collen
Desire
D
Janssens
Stefan P
SP
D000818:Animals; D017209:Apoptosis; D042783:Endothelial Cells / Q000502:physiology; D015316:Genetic Therapy; D006439:Hemodynamics; D007962:Leukocytes / Q000502:physiology; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D013552:Swine; D019076:Transgenes
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III