title: Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization.
abstract: Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic back-conversion, polyamines are oxidized and release H(2)O(2), which can cause apoptosis by mitochondrial membrane depolarization. We hypothesized that this mechanism is induced by H. pylori in macrophages. Polyamine oxidation can occur by acetylation of spermine or spermidine by spermidine/spermine N(1)-acetyltransferase prior to back-conversion by acetylpolyamine oxidase, but recently direct conversion of spermine to spermidine by the human polyamine oxidase h1, also called spermine oxidase, has been demonstrated. H. pylori induced expression and activity of the mouse homologue of this enzyme (polyamine oxidase 1 (PAO1)) by 6 h in parallel with ornithine decarboxylase, consistent with the onset of apoptosis, while spermidine/spermine N(1)-acetyltransferase activity was delayed until 18 h when late stage apoptosis had already peaked. Inhibition of PAO1 by MDL 72527 or by PAO1 small interfering RNA significantly attenuated H. pylori-induced apoptosis. Inhibition of PAO1 also significantly reduced H(2)O(2) generation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. Overexpression of PAO1 by transient transfection induced macrophage apoptosis. The importance of H(2)O(2) was confirmed by inhibition of apoptosis with catalase. These studies demonstrate a new mechanism for pathogen-induced oxidative stress in macrophages in which activation of PAO1 leads to H(2)O(2) release and apoptosis by a mitochondrial-dependent cell death pathway, contributing to deficiencies in host defense in diseases such as H. pylori infection.
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.forename: Françoise I
authors.initials: FI
authors.lastname: Bussière
authors.forename: Hangxiu
authors.initials: H
authors.lastname: Xu
authors.forename: Alain P
authors.initials: AP
authors.lastname: Gobert
authors.forename: Amy
authors.initials: A
authors.lastname: Hacker
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004790:Enzyme Induction / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D016481:Helicobacter Infections / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016480:Helicobacter pylori; D006861:Hydrogen Peroxide / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000382:microbiology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism*; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D053148:Caspase 3; D020169:Caspases; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D009955:Ornithine Decarboxylase; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse