title: Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level.
abstract: The aim was to determine whether treatment with BAY 60-2770, a selective activator of oxidized soluble guanylate cyclase (sGC), near the end of an ischemic event would prevent postischemic inflammation and mitochondrial dysfunction in wild-type (WT) and heme oxygenase-1 KO (HO-1(-/-)) mice. This protocol prevented increases in leukocyte rolling (LR) and adhesion (LA) to intestinal venules along with elevated TNFα and circulating neutrophil levels that accompany ischemia-reperfusion (I/R) in both animal models. We further hypothesized that a component of BAY 60-2770 treatment involves maintenance of mitochondrial membrane integrity during I/R. Measurements on isolated enterocytes of calcein fluorescence (mitochondrial permeability) and JC-1 fluorescence ratio (mitochondrial membrane potential) were reduced by I/R, indicating formation of mitochondrial permeability transition pores (mPTP). These effects were abrogated by BAY 60-2770 as well as cyclosporin A and SB-216763, which prevented mPTP opening and inhibited glycogen synthase kinase-3β (GSK-3β), respectively. Western blots of WT and HO-1(-/-) enterocytes indicated that GSK-3β phosphorylation on Ser(9) (inhibitory site) was reduced by half following I/R alone (increased GSK-3β activity) and increased by one-third (reduced GSK-3β activity) following BAY 60-2770. Other investigators have associated phosphorylation of the GSK-3β substrate cyclophilin D (pCyPD) with mPTP formation. We observed a 60% increase in pCyPD after I/R, whereas BAY 60-2770 treatment of sham and I/R groups reduced pCyPD by about 20%. In conclusion, selective activation of oxidized sGC of WT and HO-1(-/-) during ischemia protects against I/R-induced inflammation and preserves mucosal integrity in part by reducing pCyPD production and mPTP formation.
authors.affiliation: Department of Medical Pharmacology and Physiology; and.
authors.forename: Derek Z
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: Department of Medical Pharmacology and Physiology; and Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri jonesa@health.missouri.edu.
authors.forename: Allan W
authors.initials: AW
authors.lastname: Jones
authors.affiliation: Department of Medical Pharmacology and Physiology; and.
authors.forename: Walter Z
authors.initials: WZ
authors.lastname: Wang
authors.affiliation: Department of Medical Pharmacology and Physiology; and.
authors.forename: Meifang
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medical Pharmacology and Physiology; and Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Korthuis
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007422:Intestines / Q000098:blood supply / Q000166:cytology; D007511:Ischemia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*
chemical_list: C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D006845:Hydrocarbons, Fluorinated; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D051547:Heme Oxygenase-1; D000071679:Glycogen Synthase Kinase 3 beta; D000071756:Soluble Guanylyl Cyclase; D021983:Cyclophilins
keywords: adenosine 5′-triphosphate synthase; bay 60-2770; cyclophilin D; cyclosporine A; glycogen synthase kinase-3β; heme oxygenase-1; ischemia-reperfusion; leukocyte rolling and adhesion; mitochondrial permeability transition pore; protein kinase G