Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors
Por:
Galan, M, Varona, S, Orriols, M, Rodriguez, JA, Aguilo, S, Dilme, J, Camacho, M, Martinez-Gonzalez, J, Rodriguez, C
Publicada:
1 may 2016
Resumen:
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.
Filiaciones:
Galan, M:
Inst Invest Biomed IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona 08025, Spain
Varona, S:
Inst Invest Biomed IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona 08025, Spain
Orriols, M:
Inst Invest Biomed IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona 08025, Spain
Rodriguez, JA:
Univ Navarra, Lab Atherothrombosis, Program Cardiovasc Dis, Ctr Appl Med Res, Pamplona 31008, Spain
Aguilo, S:
Inst Invest Biomed IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona 08025, Spain
Dilme, J:
Inst Invest Biomed IIB St Pau, Lab Angiol Biol Vasc & Inflamac, Barcelona 08025, Spain
Inst Invest Biomed IIB St Pau, Serv Cirugia Vasc, Barcelona 08025, Spain
Camacho, M:
Inst Invest Biomed IIB St Pau, Lab Angiol Biol Vasc & Inflamac, Barcelona 08025, Spain
Inst Invest Biomed IIB St Pau, Serv Cirugia Vasc, Barcelona 08025, Spain
Martinez-Gonzalez, J:
Inst Invest Biomed IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona 08025, Spain
Rodriguez, C:
Inst Invest Biomed IIB St Pau, Ctr Invest Cardiovasc CSIC ICCC, Barcelona 08025, Spain
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