title: Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors.
abstract: Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression.
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain.
authors.forename: Saray
authors.initials: S
authors.lastname: Varona
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Orriols
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Rodríguez
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Aguiló
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Dilmé
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Camacho
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain jmartinez@csic-iccc.org crodriguezs@csic-iccc.org.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica (IIB-Sant Pau), 08025 Barcelona, Spain jmartinez@csic-iccc.org crodriguezs@csic-iccc.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodriguez
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000201:enzymology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D012720:Severity of Illness Index; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006655:Histone Deacetylases
keywords: Abdominal aortic aneurysm; Histone deacetylases; Inflammation; Metalloproteinases; Vascular remodelling