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A Novel Agent with Histone Deacetylase Inhibitory Activity Attenuates Neointimal Hyperplasia

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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.

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Acknowledgments

This research was supported in-part by the Monash University Strategic Grant Scheme.

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Authors and Affiliations

  1. Australian Centre for Blood Diseases, Department of Medicine, Translational Research Division, Eastern Clinical Research Unit, AMREP Facility, Monash University, 6th Floor Burnet Tower, 89 Commercial Rd, Prahran 3181, Melbourne, VIC, Australia

    M. Rahmatzadeh, H. B. Liu & A. E. Dear

  2. Queensland Research Center for Peripheral Vascular Diseases, School of Medicine & Dentistry, James Cook University, Townsville, QLD, Australia

    S. M. Krishna

  3. Department of Pharmacology, Monash University, Wellington Rd, Clayton 3168, Melbourne, VIC, Australia

    T. A. Gaspari, I. Welungoda & R. E. Widdop

  4. Eastern Health Clinical School, Monash University, Box Hill Hospital, Level 2, 5 Arnold Street, Box Hill 3128, Melbourne, VIC, Australia

    A. E. Dear

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  1. M. Rahmatzadeh
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Corresponding author

Correspondence to A. E. Dear.

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Supplementary Fig. 1

MCT-3 treatment induced expression of PAI-1 in partially ligated (L) carotid arteries. Confocal equi-exposure images of carotid arteries immunolabelled for PAI-1 (see yellow arrows) 21 days after partial ligation (2 millisecond exposure, x20-40). n = 1–2. (PPTX 128 kb)

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Rahmatzadeh, M., Liu, H.B., Krishna, S.M. et al. A Novel Agent with Histone Deacetylase Inhibitory Activity Attenuates Neointimal Hyperplasia. Cardiovasc Drugs Ther 28, 395–406 (2014). https://doi.org/10.1007/s10557-014-6540-y

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