title: 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.affiliation: Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. sun1@mail.nih.gov
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.forename: Angel M
authors.initials: AM
authors.lastname: Aponte
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kohr
authors.forename: Guang
authors.initials: G
authors.lastname: Tong
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage; D002227:Carbazoles / Q000008:administration & dosage; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D015538:Nitrosation; D009924:Organ Culture Techniques; D010069:Oxadiazoles / Q000008:administration & dosage; D011810:Quinoxalines / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D002227:Carbazoles; D010069:Oxadiazoles; D011810:Quinoxalines; C073601:KT 5823; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D001205:Ascorbic Acid; D019331:NG-Nitroarginine Methyl Ester