TY - JOUR
T1 - Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion
AU - Obal, Detlef
AU - Dai, Shujing
AU - Keith, Rachel
AU - Dimova, Neviana
AU - Kingery, Justin
AU - Zheng, Yu Ting
AU - Zweier, Jay
AU - Velayutham, Murugesan
AU - Prabhu, Sumanth D.
AU - Li, Qianghong
AU - Conklin, Daniel
AU - Yang, Dan
AU - Bhatnagar, Aruni
AU - Bolli, Roberto
AU - Rokosh, Gregg
N1 - Publisher Copyright:
© The Author(s) 2012.
PY - 2012/11
Y1 - 2012/11
N2 - 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 myocytespecific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocytespecific 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.
AB - 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 myocytespecific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocytespecific 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.
KW - Cardioprotection
KW - Extracellular superoxide dismutase
KW - Ischemia/reperfusion injury
KW - NO-bioavailability
KW - Peroxynitrite
UR - http://www.scopus.com/inward/record.url?scp=84867682862&partnerID=8YFLogxK
U2 - 10.1007/s00395-012-0305-1
DO - 10.1007/s00395-012-0305-1
M3 - Article
C2 - 23099819
AN - SCOPUS:84867682862
SN - 0300-8428
VL - 107
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 6
M1 - 305
ER -