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Open Access 01-11-2012 | Original Contribution

Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion

Authors: Detlef Obal, Shujing Dai, Rachel Keith, Neviana Dimova, Justin Kingery, Yu-Ting Zheng, Jay Zweier, Murugesan Velayutham, Sumanth D. Prabhu, Qianghong Li, Daniel Conklin, Dan Yang, Aruni Bhatnagar, Roberto Bolli, Gregg Rokosh

Published in: Basic Research in Cardiology | Issue 6/2012

Abstract

Increased levels of extracellular superoxide dismutase (ecSOD) induced by preconditioning or gene therapy protect the heart from ischemia/reperfusion injury. To elucidate the mechanism responsible for this action, we studied the effects of increased superoxide scavenging on nitric oxide (NO) bioavailability in a cardiac myocyte-specific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocyte-specific ecSOD activity 27.5-fold. Transgenic ecSOD was localized to the sarcolemma and, notably, the cytoplasm of cardiac myocytes. Ischemia/reperfusion injury was attenuated in ecSOD Tg hearts, in which infarct size was decreased and LV functional recovery was improved. Using the ROS spin trap, DMPO, electron paramagnetic resonance (EPR) spectroscopy demonstrated a significant decrease in ROS in Tg hearts during the first 20 min of reperfusion. This decrease in ROS was accompanied by an increase in NO production determined by EPR using the NO spin trap, Fe-MGD. Attenuated ROS in ecSOD Tg myocytes was also supported by decreased production of peroxynitrite (ONOO⁻). Increased NO bioavailability was confirmed by attenuated guanylate cyclase-dependent (p-VASP) signaling. In conclusion, attenuation of ROS levels by cardiac-specific ecSOD overexpression increases NO bioavailability in response to ischemia/reperfusion and protects against reperfusion injury. These findings are the first to demonstrate increased NO bioavailability with attenuation of ROS by direct measurement of these reactive species (EPR, reactive fluorescent dyes) with cardiac-specific ecSOD expression. This is also the first indication that the predominantly extracellular SOD isoform is capable of cytosolic localization that affects myocardial intracellular signal transduction and function.

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Title: Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion
Authors: Detlef Obal
Shujing Dai
Rachel Keith
Neviana Dimova
Justin Kingery
Yu-Ting Zheng
Jay Zweier
Murugesan Velayutham
Sumanth D. Prabhu
Qianghong Li
Daniel Conklin
Dan Yang
Aruni Bhatnagar
Roberto Bolli
Gregg Rokosh
Publication date: 01-11-2012
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 6/2012
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0305-1

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Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion

Abstract

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Abstract

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