Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.
Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):851-60. doi: 10.1161/ATVBAHA.110.221952. Epub 2011 Jan 13.
Proliferation of smooth muscle cells (SMC) in response to vascular injury is central to neointimal vascular remodeling. There is accumulating evidence that histone acetylation constitutes a major epigenetic modification for the transcriptional control of proliferative gene expression; however, the physiological role of histone acetylation for proliferative vascular disease remains elusive.
In the present study, we investigated the role of histone deacetylase (HDAC) inhibition in SMC proliferation and neointimal remodeling. We demonstrate that mitogens induce transcription of HDAC 1, 2, and 3 in SMC. Short interfering RNA-mediated knockdown of either HDAC 1, 2, or 3 and pharmacological inhibition of HDAC prevented mitogen-induced SMC proliferation. The mechanisms underlying this reduction of SMC proliferation by HDAC inhibition involve a growth arrest in the G(1) phase of the cell cycle that is due to an inhibition of retinoblastoma protein phosphorylation. HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip). Furthermore, HDAC inhibition repressed mitogen-induced cyclin D1 mRNA expression and cyclin D1 promoter activity. As a result of this differential cell cycle-regulatory gene expression by HDAC inhibition, the retinoblastoma protein retains a transcriptional repression of its downstream target genes required for S phase entry. Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury.
These findings identify HDAC as a critical component of a transcriptional cascade regulating SMC proliferation and suggest that HDAC might play a pivotal role in the development of proliferative vascular diseases, including atherosclerosis and in-stent restenosis.
血管损伤后平滑肌细胞（SMC）的增殖是血管内膜重塑的核心。有越来越多的证据表明，组蛋白乙酰化是转录控制增殖基因表达的主要表观遗传修饰；然而，组蛋白乙酰化在增殖性血管疾病中的生理作用仍不清楚。
在本研究中，我们研究了组蛋白去乙酰化酶（HDAC）抑制在 SMC 增殖和新内膜重塑中的作用。我们证明有丝分裂原诱导 SMC 中 HDAC1、2 和 3 的转录。用短发夹 RNA 敲低 HDAC1、2 或 3 或用药物抑制 HDAC 可防止有丝分裂原诱导的 SMC 增殖。HDAC 抑制减少 SMC 增殖的机制涉及细胞周期 G1 期的生长停滞，这是由于视网膜母细胞瘤蛋白磷酸化的抑制。HDAC 抑制导致细胞周期依赖性激酶抑制剂 p21（Cip1）和 p27（Kip）的转录和转录后调节。此外，HDAC 抑制抑制有丝分裂原诱导的 cyclin D1 mRNA 表达和 cyclin D1 启动子活性。由于 HDAC 抑制对细胞周期调节基因表达的这种差异，视网膜母细胞瘤蛋白保留了其下游靶基因的转录抑制，这些靶基因是 S 期进入所必需的。最后，我们通过证明 HDAC 抑制可减少血管损伤小鼠模型中的新内膜形成和 cyclin D1 的表达，提供了这些观察结果在体内适用的证据。
这些发现将 HDAC 鉴定为调节 SMC 增殖的转录级联反应的关键组成部分，并表明 HDAC 可能在增殖性血管疾病的发展中发挥关键作用，包括动脉粥样硬化和支架内再狭窄。
