Essential role of nitric oxide in acute ischemic preconditioning: S-nitros(yl)ation versus sGC/cGMP/PKG signaling?

Abstract

Nitric oxide (NO) plays an important role in acute ischemic preconditioning (IPC). In addition to activating soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling pathways, NO-mediated protein S-nitros(yl)ation (SNO) has been recently shown to play an essential role in cardioprotection against ischemia-reperfusion (I/R) injury. In our previous studies, we have shown that IPC-induced cardioprotection could be blocked by treatment with either N-nitro-L-arginine methyl ester (L-NAME, a constitutive NO synthase inhibitor) or ascorbate (a reducing agent to decompose SNO). To clarify NO-mediated sGC/cGMP/PKG-dependent or -independent (i.e., SNO) signaling involved in IPC-induced cardioprotection, mouse hearts were Langendorff-perfused in the dark to prevent SNO decomposition by light exposure. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, a highly selective inhibitor of sGC) or KT5823 (a potent and selective inhibitor of PKG) did not abolish IPC-induced acute protection, suggesting that the sGC/cGMP/PKG signaling pathway does not play an important role in NO-mediated cardioprotective signaling during acute IPC. In addition, treatment with ODQ in IPC hearts provided an additional protective effect on functional recovery, in parallel with a higher SNO level in these ODQ+IPC hearts. In conclusion, these results suggest that the protective effect of NO is not related primarily to activation of the sGC/cGMP/PKG signaling pathway, but rather through SNO signaling in IPC-induced acute cardioprotection.

• Authors: Junhui Sun, Angel M Aponte, Mark J Kohr, Guang Tong, Charles Steenbergen, Elizabeth Murphy
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 54 Pg. 105-12 (Jan 2013) ISSN: 1873-4596 [Electronic] United States
• PMID: 22989471 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
• Carbazoles
• Oxadiazoles
• Quinoxalines
• KT 5823
• Nitric Oxide
• Cyclic GMP-Dependent Protein Kinases
• Guanylate Cyclase
• Ascorbic Acid
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Ascorbic Acid (administration & dosage)
• Carbazoles (administration & dosage)
• Cells, Cultured
• Cyclic GMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Guanylate Cyclase (antagonists & inhibitors, metabolism)
• Ischemic Preconditioning, Myocardial
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism, pathology)
• NG-Nitroarginine Methyl Ester (administration & dosage)
• Nitric Oxide (metabolism)
• Nitrosation
• Organ Culture Techniques
• Oxadiazoles (administration & dosage)
• Quinoxalines (administration & dosage)
• Reperfusion Injury (prevention & control)
• Signal Transduction