Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression

• Published in: PloS one 2016-02, Vol.11 (2), p.e0149288-e0149288
• Main Authors: Azuma, Junya, Wong, Ronald J, Morisawa, Takeshi, Hsu, Mark, Maegdefessel, Lars, Zhao, Hui, Kalish, Flora, Kayama, Yosuke, Wallenstein, Matthew B, Deng, Alicia C, Spin, Joshua M, Stevenson, David K, Dalman, Ronald L, Tsao, Philip S
• Format: Article
• Language: English
• Subjects: Abdominal aortic aneurysm; Aneurysms; Angiotensin II; Animals; Aorta; Aortic Aneurysm, Abdominal - drug therapy; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Aortic aneurysms; Apolipoprotein E; Biology and Life Sciences; Body Weight; Cytokines; Cytokines - genetics; Cytokines - metabolism; Development and progression; Disease Models, Animal; Disease Progression; Elastase; Enzyme Activation; Gene Expression; Genes, Reporter; Genetic aspects; Heme; Heme - metabolism; Heme - pharmacology; Heme oxygenase (decyclizing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hydroxymethylglutaryl-CoA reductase; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Inflammation; Inflammation Mediators - metabolism; Interleukin 1; Interleukin 10; Interleukin 6; Lipids - blood; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Male; Medicin och hälsovetenskap; Medicine and Health Sciences; Mice; Mice, Knockout; Monocyte chemoattractant protein 1; Nitric oxide; Oxidases; Oxygenase; Pancreas; Pancreatic elastase; Peritoneum; Physicians; Physiological aspects; Promoter Regions, Genetic; Research and Analysis Methods; Rodents; Statins; Swine; Transforming growth factor-b; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149288

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.