title: Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.
abstract: Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morisawa
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Hsu
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Flora
authors.initials: F
authors.lastname: Kalish
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States of America.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kayama
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wallenstein
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States of America.
authors.forename: Alicia C
authors.initials: AC
authors.lastname: Deng
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
authors.affiliation: Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Dalman
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.|Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States of America.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001835:Body Weight; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D015870:Gene Expression; D017930:Genes, Reporter; D006418:Heme / Q000378:metabolism / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D013552:Swine
chemical_list: D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008055:Lipids; D006418:Heme; D051547:Heme Oxygenase-1