Department of Physiology, Peking University, Beijing, China.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2676-84. doi: 10.1161/ATVBAHA.111.230888.
Vascular smooth muscle cell (SMC) proliferation has an indispensable role in the pathogenesis of vascular disease, but the mechanism is not fully elucidated. The epigenetic enzyme histone deacetylase 7 (HDAC7) is involved in endothelial homeostasis and SMC differentiation and could have a role in SMC proliferation. In this study, we sought to examine the effect of 2 HDAC7 isoforms on SMC proliferation and neointima formation.
We demonstrated that overexpression of unspliced HDAC7 (HDAC7u) could suppress SMC proliferation through downregulation of cyclin D1 and cell cycle arrest, whereas spliced HDAC7 (HDAC7s) could not. Small interfering RNA (siRNA)-mediated knockdown of HDAC7 increased SMC proliferation and induced nuclear translocation of β-catenin. Additional experiments showed that only HDAC7u could bind to β-catenin and retain it in the cytoplasm. Reporter gene assay and reverse transcription polymerase chain reaction revealed a reduction of β-catenin activity in cells overexpressing HDAC7u but not HDAC7s. Deletion studies indicated that the C-terminal region of HDAC7u is responsible for the interaction with β-catenin. However, the addition of amino acids to the N terminus of HDAC7u disrupted the binding, further strengthening our hypothesis that HDAC7s does not interact with β-catenin. The growth factor platelet-derived growth factor-BB increased the splicing of HDAC7 while simultaneously decreasing the expression of HDAC7u. Importantly, in an animal model of femoral artery wire injury, we demonstrated that knockdown of HDAC7 by siRNA aggravates neointima formation in comparison with control siRNA.
Our findings demonstrate that splicing of HDAC7 modulates SMC proliferation and neointima formation through β-catenin nuclear translocation, which provides a potential therapeutic target in vascular disease.
血管平滑肌细胞（SMC）增殖在血管疾病的发病机制中起着不可或缺的作用，但机制尚未完全阐明。表观遗传酶组蛋白去乙酰化酶 7（HDAC7）参与内皮稳态和 SMC 分化，并且可能在 SMC 增殖中起作用。在这项研究中，我们试图研究 2 种 HDAC7 同工型对 SMC 增殖和新生内膜形成的影响。
我们证明，未剪接的 HDAC7（HDAC7u）的过表达可以通过下调细胞周期蛋白 D1 和细胞周期停滞来抑制 SMC 增殖，而剪接的 HDAC7（HDAC7s）则不能。小干扰 RNA（siRNA）介导的 HDAC7 敲低增加了 SMC 增殖并诱导 β-连环蛋白的核易位。进一步的实验表明，只有 HDAC7u 可以与 β-连环蛋白结合并将其保留在细胞质中。报告基因测定和逆转录聚合酶链反应显示，HDAC7u 过表达的细胞中 β-连环蛋白活性降低，但 HDAC7s 则不然。缺失研究表明，HDAC7u 的 C 端区域负责与 β-连环蛋白相互作用。然而，将氨基酸添加到 HDAC7u 的 N 端会破坏结合，进一步加强了我们的假设，即 HDAC7s 不与 β-连环蛋白相互作用。生长因子血小板衍生生长因子-BB 增加了 HDAC7 的剪接，同时降低了 HDAC7u 的表达。重要的是，在股动脉线损伤的动物模型中，我们证明与对照 siRNA 相比，siRNA 敲低 HDAC7 会加重新生内膜形成。
我们的研究结果表明，HDAC7 的剪接通过 β-连环蛋白核易位调节 SMC 增殖和新生内膜形成，这为血管疾病提供了一个潜在的治疗靶点。
