title: Atrial natriuretic peptide prevents the mitochondrial permeability transition pore opening by inactivating glycogen synthase kinase 3β via PKG and PI3K in cardiac H9c2 cells.
abstract: The purpose of this study was to test if atrial natriuretic peptide (ANP) can prevent the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3β (GSK-3β). ANP prevented loss of mitochondrial membrane potential (ΔΨ(m)) caused by H(2)O(2) in a dose-dependent manner. Similarly, cyclosporin A, an inhibitor of the mPTP opening, could also preserve ΔΨ(m). ANP increased GSK-3β phosphorylation at Ser(9), pointing to that ANP inactivates GSK-3β. ANP could not prevent the loss of ΔΨ(m) in cells transfected with the constitutively active GSK-3β (GSK-3β-S9A) mutant. The effects of ANP on GSK-3β phosphorylation and ΔΨ(m) were reversed by the selective PKG inhibitor KT5823 [2,3,9,10,11,12-hexahydro-10R-methoxy-2,9-dimethyl-1-oxo-9S,12R-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester]. In support, PKG markedly enhanced GSK-3β phosphorylation. ANP-induced GSK-3β phosphorylation was also abolished by the PI3K inhibitor LY294002 [2-(4-morpholinyl-4H-1-benzopyran-4-one hydrochloride)] and ANP could not prevent H(2)O(2)-induced loss of ΔΨ(m) in the presence of LY294002. These data suggest that ANP modulates the mPTP opening by inactivating GSK-3β through PKG and PI3K. GSK-3β is a common downstream target of PKG and PI3K. Prevention of the mPTP opening may underlie the mechanism for ANP's protection against reperfusion injury.
authors.affiliation: Department of Physiology, College of Medicine, Yanbian University, Yanji, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Hong
authors.forename: Jinkun
authors.initials: J
authors.lastname: Xi
authors.forename: Yidong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Jingman
authors.initials: J
authors.lastname: Xu
authors.forename: Xun
authors.initials: X
authors.lastname: Cui
authors.forename: Zhelong
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002460:Cell Line; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019869:Phosphatidylinositol 3-Kinases; C000605508:Gsk3b protein, rat