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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalBasic Research in Cardiology
Volume107
Issue number6
DOIs
StateAccepted/In press - Nov 2012
Externally publishedYes

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Cardiac Myocytes
Biological Availability
Superoxide Dismutase
Reperfusion
Nitric Oxide
Ischemia
Electron Spin Resonance Spectroscopy
Reperfusion Injury
Sarcolemma
Peroxynitrous Acid
Fluorescent Dyes
Superoxides
Genetic Therapy
Muscle Cells
Transgenic Mice
Signal Transduction
Spectrum Analysis
Protein Isoforms
Cytoplasm

Keywords

  • Cardioprotection
  • Extracellular superoxide dismutase
  • Ischemia/reperfusion injury
  • NO-bioavailability
  • Peroxynitrite

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Physiology

Cite this

Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion. / Obal, Detlef; Dai, Shujing; Keith, Rachel; Dimova, Neviana; Kingery, Justin; Zheng, Yu Ting; Zweier, Jay; Velayutham, Murugesan; Prabhu, Sumanth D.; Li, Qianghong; Conklin, Daniel; Yang, Dan; Bhatnagar, Aruni; Bolli, Roberto; Rokosh, Gregg.

In: Basic Research in Cardiology, Vol. 107, No. 6, 11.2012, p. 1-14.

Research output: Contribution to journalArticle

Obal, D, Dai, S, Keith, R, Dimova, N, Kingery, J, Zheng, YT, Zweier, J, Velayutham, M, Prabhu, SD, Li, Q, Conklin, D, Yang, D, Bhatnagar, A, Bolli, R & Rokosh, G 2012, 'Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion', Basic Research in Cardiology, vol. 107, no. 6, pp. 1-14. https://doi.org/10.1007/s00395-012-0305-1
Obal, Detlef ; Dai, Shujing ; Keith, Rachel ; Dimova, Neviana ; Kingery, Justin ; Zheng, Yu Ting ; Zweier, Jay ; Velayutham, Murugesan ; Prabhu, Sumanth D. ; Li, Qianghong ; Conklin, Daniel ; Yang, Dan ; Bhatnagar, Aruni ; Bolli, Roberto ; Rokosh, Gregg. / Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion. In: Basic Research in Cardiology. 2012 ; Vol. 107, No. 6. pp. 1-14.
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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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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

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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 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.

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 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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