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Cardioselective nitric oxide synthase 3 gene transfer protects against myocardial reperfusion injury

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Abstract

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 × 1010 PFU, n = 13) or control vector (AdRR5, 5 × 1010 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.

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Acknowledgments

This work was supported by a scholarship from the K.U. Leuven and the Soros Foundation Hungary (Dr. Szelid) and by Research Fund of K.U. Leuven GOA/2007/13 (Dr. Janssens and Dr. Pokreisz). Dr. Stefan Janssens is a Principal Investigator of the Flanders Institute for Biotechnology (VIB) and holder of a chair in cardiology sponsored by Astra Zeneca.

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Authors and Affiliations

  1. Vesalius Research Center, Flanders Institute for Biotechnology (VIB), Leuven, Belgium

    Zsolt Szelid, Peter Pokreisz, Xiaoshun Liu, Pieter Vermeersch, Glenn Marsboom, Hilde Gillijns, Marijke Pellens, Desire Collen & Stefan P. Janssens

  2. Department of Cardiovascular Diseases, K.U. Leuven, Leuven, Belgium

    Zsolt Szelid, Peter Pokreisz, Xiaoshun Liu, Frans Van de Werf & Stefan P. Janssens

  3. Heart Center, Semmelweis University, Budapest, Hungary

    Zsolt Szelid

  4. Department of Medical Diagnostic Sciences, K.U. Leuven, Leuven, Belgium

    Erik Verbeken

  5. Vesalius Research Center, VIB and Department of Cardiology, Gasthuisberg University Hospital, K.U. Leuven, 49 Herestraat, 3000, Leuven, Belgium

    Stefan P. Janssens

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  1. Zsolt Szelid
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  2. Peter Pokreisz
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  9. Frans Van de Werf
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  11. Stefan P. Janssens
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Correspondence to Stefan P. Janssens.

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Z. Szelid and P. Pokreisz contributed equally to the study.

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Szelid, Z., Pokreisz, P., Liu, X. et al. Cardioselective nitric oxide synthase 3 gene transfer protects against myocardial reperfusion injury. Basic Res Cardiol 105, 169–179 (2010). https://doi.org/10.1007/s00395-009-0077-4

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