title: Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm.
abstract: Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved.
  
  
  
  Male ApoE(-/-) mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks.
  
  
  
  Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining.
  
  
  
  Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Emina
authors.initials: E
authors.lastname: Vorkapic
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Elma
authors.initials: E
authors.lastname: Dugic
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.affiliation: Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joy
authors.initials: J
authors.lastname: Roy
authors.affiliation: Department of Pathology, University of Helsinki, Helsinki, Finland; HUSLAB, Division of Pathology, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Mäyränpää
authors.affiliation: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden. Electronic address: dick.wagsater@liu.se.
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D001011:Aorta / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy*; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D053818:Chymases / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D007249:Inflammation; D008297:Male; D008407:Mast Cells / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D017252:CD3 Complex; C485468:Cd3e protein, mouse; D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D053818:Chymases
keywords: Abdominal aortic aneurysm; Angiotensin II; Imatinib; Vascular inflammation