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The Effects of Modulating eNOS Activity and Coupling in Ischemia/Reperfusion (I/R)
Naunyn-Schmiedeberg's Archives of Pharmacology
  • Kerry-Anne Perkins, Philadelphia College of Osteopathic Medicine
  • Sailesh Pershad, Philadelphia College of Osteopathic Medicine
  • Qian Chen, Philadelphia College of Osteopathic Medicine
  • Sloane McGraw, Philadelphia College of Osteopathic Medicine
  • Jovan S Adams, Philadelphia College of Osteopathic Medicine
  • Christopher Zambrano, Philadelphia College of Osteopathic Medicine
  • Samuel Krass, Philadelphia College of Osteopathic Medicine
  • Jeffrey Emrich, Philadelphia College of Osteopathic Medicine
  • Brandon Bell, Philadelphia College of Osteopathic Medicine
  • Michael Lyamu, Philadelphia College of Osteopathic Medicine
  • Catherine Prince, Philadelphia College of Osteopathic Medicine
  • Helen Kay, Philadelphia College of Osteopathic Medicine
  • Jane Chun-wen Teng, Philadelphia College of Osteopathic Medicine
  • Lindon H. Young, Philadelphia College of Osteopathic Medicine
Document Type
Article
Publication Date
1-1-2012
Abstract
The in vivo role of endothelial nitric oxide synthase (eNOS) uncoupling mediating oxidative stress in ischemia/reperfusion (I/R) injury has not been well established. In vitro, eNOS coupling refers to the reduction of molecular oxygen to L-arginine oxidation and generation of L-citrulline and nitric oxide NO synthesis in the presence of an essential cofactor, tetrahydrobiopterin (BH(4)). Whereas uncoupled eNOS refers to that the electron transfer becomes uncoupled to L-arginine oxidation and superoxide is generated when the dihydrobiopterin (BH(2)) to BH(4) ratio is increased. Superoxide is subsequently converted to hydrogen peroxide (H(2)O(2)). We tested the hypothesis that promoting eNOS coupling or attenuating uncoupling after I/R would decrease H(2)O(2)/increase NO release in blood and restore postreperfused cardiac function. We combined BH(4) or BH(2) with eNOS activity enhancer, protein kinase C epsilon (PKC ε) activator, or eNOS activity reducer, PKC ε inhibitor, in isolated rat hearts (ex vivo) and femoral arteries/veins (in vivo) subjected to I(20 min)/R(45 min). When given during reperfusion, PKC ε activator combined with BH(4), not BH(2), significantly restored postreperfused cardiac function and decreased leukocyte infiltration (p < 0.01) while increasing NO (p < 0.05) and reducing H(2)O(2) (p < 0.01) release in femoral I/R veins. These results provide indirect evidence suggesting that PKC ε activator combined with BH(4) enhances coupled eNOS activity, whereas it enhanced uncoupled eNOS activity when combined with BH(2). By contrast, the cardioprotective and anti-oxidative effects of the PKC ε inhibitor were unaffected by BH(4) or BH(2) suggesting that inhibition of eNOS uncoupling during reperfusion following sustained ischemia may be an important mechanism.
PubMed ID
21947254
Comments

This article was published in Naunyn-Schmiedeberg's Archives of Pharmacology,Volume 385, Issue 1, January 2012, pages 27-38.

The published version is available at http://dx.doi.org/10.1007/s00210-011-0693-z

Copyright © 2011 Springer-Verlag

Citation Information
Kerry-Anne Perkins, Sailesh Pershad, Qian Chen, Sloane McGraw, et al.. "The Effects of Modulating eNOS Activity and Coupling in Ischemia/Reperfusion (I/R)" Naunyn-Schmiedeberg's Archives of Pharmacology Vol. 385 Iss. 1 (2012) p. 27 - 38
Available at: http://works.bepress.com/qian_chen/29/