title: Paraoxonase-1 overexpression prevents experimental abdominal aortic aneurysm progression.
abstract: Abdominal aortic aneurysm (AAA) is a permanent dilation of the aorta due to excessive proteolytic, oxidative and inflammatory injury of the aortic wall. We aimed to identify novel mediators involved in AAA pathophysiology, which could lead to novel therapeutic approaches. For that purpose, plasma from four AAA patients and four controls were analysed by a label-free proteomic approach. Among identified proteins, paraoxonase-1 (PON1) was decreased in plasma of AAA patients compared with controls, which was further validated in a bigger cohort of samples by ELISA. The phenylesterase enzymatic activity of PON1 was also decreased in serum of AAA patients compared with controls. To address the potential role of PON1 as a mediator of AAA, experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and human transgenic PON1 (HuTgPON1) mice. Similar to humans, PON1 activity was also decreased in serum of elastase-induced AAA mice compared with healthy mice. Interestingly, overexpression of PON1 was accompanied by smaller aortic dilation and higher elastin and vascular smooth muscle cell (VSMC) content in the AAA of HuTgPON1 compared with WT mice. Moreover, HuTgPON1 mice display decreased oxidative stress and apoptosis, as well as macrophage infiltration and monocyte chemoattractant protein-1 (MCP1) expression, in elastase-induced AAA. In conclusion, decreased circulating PON1 activity is associated with human and experimental AAA. PON1 overexpression in mice protects against AAA progression by reducing oxidative stress, apoptosis and inflammation, suggesting that strategies aimed at increasing PON1 activity could prevent AAA.
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Burillo
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Tarin
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Monica-Maria
authors.initials: MM
authors.lastname: Torres-Fonseca
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Carlos-Ernesto
authors.initials: CE
authors.lastname: Fernandez-García
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Roxana
authors.initials: R
authors.lastname: Martinez-Pinna
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Martinez-Lopez
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Llamas-Granda
authors.affiliation: Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Camafeita
authors.affiliation: Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Lopez
authors.affiliation: Hospital de Galdakao, Vizcaya, Spain.
authors.forename: Melina
authors.initials: M
authors.lastname: Vega de Ceniga
authors.affiliation: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: Luis-Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz-Autonoma University, Madrid, Spain jlmartin@fjd.es.
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Martín-Ventura
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000517:prevention & control; D017209:Apoptosis / Q000187:drug effects; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D040901:Proteomics / Q000379:methods
chemical_list: D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C560867:PON1 protein, mouse
keywords: abdominal aortic aneurysm; immune-inflammatory response; oxidative stress; paraoxonase-1; proteomics