Rahmatzadeh M, Liu H B, Krishna S M, Gaspari T A, Welungoda I, Widdop R E, Dear A E
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.
Cardiovasc Drugs Ther. 2014 Oct;28(5):395-406. doi: 10.1007/s10557-014-6540-y.
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.
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.
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.
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.
新生内膜增生（NIH）是在旁路移植血管和支架再狭窄中发现的一种病理生理事件，其特征是血管平滑肌细胞（VSMC）异常迁移和增殖。最近的证据表明，组蛋白脱乙酰酶调节是VSMC增殖和迁移的调节因子，也是治疗NIH的潜在治疗靶点。我们研究的目的是确定新型药物MCT-3在体外和体内调节VSMC迁移、增殖和NIH的潜力。
体外VSMC研究采用逆转录酶和实时定量PCR基因表达分析、蛋白质印迹法、酶联免疫吸附测定法以及细胞增殖和迁移划痕试验。体内研究采用NIH的部分颈动脉结扎模型以及FVB/N小鼠的免疫组织化学方法。
MCT-3处理可诱导组蛋白H3和H4乙酰化，在体外抑制VSMC迁移和增殖，并在体内显著减轻NIH。还确定了MCT-3介导的对孤儿核受体NUR77、纤溶酶原激活物抑制剂1型（PAI-1）以及细胞周期蛋白依赖性激酶抑制剂（CDKI）p21（CIP1/WAF1）和p27（KIP1）表达的调节作用。
这些观察结果共同确定了一种具有组蛋白脱乙酰酶抑制活性的新型药物MCT-3，它能够抑制NIH，并确定了造成这些作用的潜在分子机制。可能需要进行更多的临床前研究来确定该化合物的潜在临床应用价值。
