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: María Galán, Saray Varona, Mar Orriols, José Antonio Rodríguez, Silvia Aguiló, Jaume Dilmé, Mercedes Camacho, José Martínez-González, Cristina Rodriguez
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 9 Issue 5 Pg. 541-52 (05 01 2016) ISSN: 1754-8411 [Electronic] England
• PMID: 26989193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016. Published by The Company of Biologists Ltd.

Chemical References

• Apolipoproteins E
• Biomarkers
• Histone Deacetylase Inhibitors
• Angiotensin II
• Collagen
• Elastin
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Histone Deacetylases

Topics

• Angiotensin II
• Animals
• Aorta, Abdominal (drug effects, pathology)
• Aortic Aneurysm, Abdominal (drug therapy, enzymology)
• Apolipoproteins E (deficiency, metabolism)
• Biomarkers (metabolism)
• Collagen (metabolism)
• Disease Models, Animal
• Disease Progression
• Elastin (metabolism)
• Enzyme Induction (drug effects)
• Female
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Histone Deacetylases (biosynthesis, metabolism)
• Humans
• Inflammation (pathology)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Middle Aged
• Severity of Illness Index
• Up-Regulation (drug effects)