title: Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation.
abstract: Testosterone is theorized to play a major role in the pathophysiology of abdominal aortic aneurysms (AAAs) because this disease occurs primarily in men. The role of the androgen receptor (AR) in the formation of AAAs has not been well elucidated, and therefore, it is hypothesized that androgen blockade will attenuate experimental aortic aneurysm formation.
  
  
  
  Aortas of 8- to 12-week-old male C57Bl/6 wild-type (WT) mice or male AR knockout (AR(-/-)) mice were perfused with purified porcine pancreatic elastase (0.35 U/mL) to induce AAA formation. Two groups of WT male mice were treated with the AR blockers flutamide (50 mg/kg) or ketoconazole (150 mg/kg) twice daily by intraperitoneal injection. Aortas were harvested on day 14 after video micrometry was used to measure AAA diameter. Cytokine arrays and histologic analysis were performed on aortic tissue. Groups were compared using an analysis of variance and a Tukey post hoc test.
  
  
  
  Flutamide and ketoconazole treatment (mean ± standard error of the mean) attenuated AAA formation in WT mice (84.2% ± 22.8% [P = .009] and 91.5% ± 18.2% [P = .037]) compared with WT elastase (121% ± 5.23%). In addition, AR(-/-) mice showed attenuation of AAA growth (64.4% ± 22.7%; P < .0001) compared with WT elastase. Cytokine arrays of aortic tissue revealed decreased levels of proinflammatory cytokines interleukin (IL)-α, IL-6, and IL-17 in flutamide-treated and AR(-/-) groups compared with controls.
  
  
  
  Pharmacologic and genetic AR blockade cause attenuation of AAA formation. Therapies for AR blockade used in prostate cancer may provide medical treatment to halt progression of AAAs in humans.
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: John P
authors.initials: JP
authors.lastname: Davis
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Salmon
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Pope
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Akshaya
authors.initials: A
authors.lastname: Meher
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA. Electronic address: gru6n@virginia.edu.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005485:Flutamide / Q000494:pharmacology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010196:Pancreatic Elastase; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000172:deficiency* / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: C410798:AR protein, human; C000607144:AR protein, mouse; D000726:Androgen Antagonists; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D011944:Receptors, Androgen; D005485:Flutamide; D010196:Pancreatic Elastase; D007654:Ketoconazole
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