A novel agent with histone deacetylase inhibitory activity attenuates neointimal hyperplasia

Rahmatzadeh, M., Liu, H.B., Krishna, S.M., Gaspari, T.A., Welungoda, I., Widdop, R.E., and Dear, A.E. (2014) A novel agent with histone deacetylase inhibitory activity attenuates neointimal hyperplasia. Cardiovascular Drugs and Therapy, 28 (5). pp. 395-406.

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Abstract

Purpose: Neointimal hyperplasia (NIH), a pathophysiological event identified in bypass graft and stent re-stenosis, is characterised by aberrant vascular smooth muscle cell (VSMC) migration and proliferation. Recent evidence identifies histone deacetylase modulation as a regulator of VSMC proliferation and migration and a potential therapeutic target in the treatment of NIH. The purpose of our study was to determine the in vitro and in vivo potential of a novel agent, MCT-3, to modulate VSMC migration, proliferation and NIH.

Methods: In vitro VSMC studies utilized reverse transcriptase and real time Q-PCR gene expression analysis, western blot, elisa assay and cellular proliferation and migration scratch assay's. In vivo studies utilized the partial carotid artery ligation model of NIH together with immunohistochemistry in FVB/N mice.

Results: MCT-3 treatment induced histone H3 and H4 acetylation and inhibited VSMC migration and proliferation in vitro and significantly attenuated NIH in vivo. MCT-3-mediated regulation of orphan nuclear receptor NUR77, Plasminogen Activator Inhibitor Type-1 (PAI-1) and cyclin dependent kinase inhibitors (CDKI) p21CIP1/WAF1 and p27KIP1 expression was also identified.

Conclusions: Together these observations identify a novel agent, MCT-3, with histone deacetylase inhibitory activity, able to inhibit NIH and identify a potential molecular mechanism responsible for these effects. Additional pre-clinical studies may be warranted to determine the potential clinical utility of this compound.

Item ID: 34846
Item Type: Article (Refereed Research - C1)
Keywords: histone deacetylase inhibitor; vascular smooth; muscle cell; neointimal hyperplasia; plasminogen activator; inhibitor type-1; NUR77; p21CIP1/WAF1; p27KIP1
ISSN: 1573-7241
Funders: Monash University
Projects and Grants: Monash University Strategic Grant Scheme
Date Deposited: 08 Oct 2014 04:11
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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