A Novel Agent with Histone Deacetylase Inhibitory Activity Attenuates Neointimal Hyperplasia

作者：Rahmatzadeh M; Liu H B; Krishna S M; Gaspari T A; Welungoda I; Widdop R E; Dear A E^*

来源：Cardiovascular Drugs and Therapy, 2014, 28(5): 395-406.

DOI：10.1007/s10557-014-6540-y

• Histone deacetylase inhibitor
• Vascular smooth muscle cell
• Neointimal hyperplasia
• Plasminogen activator inhibitor type-1
• NUR77
• p21(CIP1/WAF1)
• p27(KIP1)

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. %26lt;br%26gt;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%26apos;s. In vivo studies utilized the partial carotid artery ligation model of NIH together with immunohistochemistry in FVB/N mice. %26lt;br%26gt;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) p21(CIP1/WAF1) and p27(KIP1) expression was also identified. %26lt;br%26gt;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.

• 出版日期2014-10