title: Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion.
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.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, University of Louisville, KY, USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Obal
authors.forename: Shujing
authors.initials: S
authors.lastname: Dai
authors.forename: Rachel
authors.initials: R
authors.lastname: Keith
authors.forename: Neviana
authors.initials: N
authors.lastname: Dimova
authors.forename: Justin
authors.initials: J
authors.lastname: Kingery
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Zheng
authors.forename: Jay
authors.initials: J
authors.lastname: Zweier
authors.forename: Murugesan
authors.initials: M
authors.lastname: Velayutham
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Qianghong
authors.initials: Q
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Conklin
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.forename: Gregg
authors.initials: G
authors.lastname: Rokosh
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D013482:Superoxide Dismutase