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Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors.

2016, Dis Model Mech. 2016 Mar 17. pii: dmm.024513. [Epub ahead of print]
Galán M1, Varona S1, Orriols M1, Rodríguez JA2, Aguiló S1, Dilmé J3, Camacho M3, Martínez-González J4, Rodriguez C4.
Autores del centro relacionados: Martínez-González Jose, Rodríguez Cristina, Aguiló Silvia.
Abstract
Clinical management of abdominal aortic aneurysms (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 HDACs 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 (class I), 4 and 7 (class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared to those from donors (n=14). Aortic aneurysms from Ang II-infused ApoE-/- mice exhibited a similar HDACs 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 patent in MC-1568-treated mice. The disorganization 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.
© 2016. Published by The Company of Biologists Ltd.
PMID: 26989193 [PubMed - as supplied by publisher]

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