Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing, China.
Mol Cell Biochem. 2014 Apr;389(1-2):169-76. doi: 10.1007/s11010-013-1938-6. Epub 2013 Dec 31.
In the recent decades, carotid angioplasty and stenting (CAS) has been developed into a credible option for the patients with carotid stenosis. However, restenosis remains a severe and unsolved issue after CAS treatment. Restenosis is characterized by neointimal hyperplasia, which is partially caused by vascular smooth muscle cells (VSMC) proliferation. However, the molecular mechanism involved in the restenosis is still unclear. In this study, we demonstrated a functional crosstalk between two TGF-β superfamily signaling pathway members, Smad3 and BMPR2, in VSMC proliferation. Smad3 plays an important role in the TGF-β/Smad3 signaling pathway, and is significantly upregulated in the carotid artery with restenosis to promote VSMC proliferation. In contrast, BMP receptor II (BMPR2), an inhibitor of VSMC proliferation is downregulated in carotid restenosis. We further found that BMPR2 downregulation is mediated by miR-17-92 cluster, which is transcriptionally regulated by Smad3. Thus, Smad3 upregulation and Smad3/miR-17-92 cluster-dependent BMPR2 downregulation are likely to promote VSMC proliferation and restenosis. Taken together, our results may provide novel clues for early diagnosis of carotid restenosis and developing new therapeutic strategy.
在最近几十年中，颈动脉血管成形术和支架置入术（CAS）已经发展成为治疗颈动脉狭窄患者的一种可靠选择。然而，在 CAS 治疗后，再狭窄仍然是一个严重且尚未解决的问题。再狭窄的特征是新生内膜增生，这部分是由血管平滑肌细胞（VSMC）增殖引起的。然而，再狭窄涉及的分子机制仍不清楚。在这项研究中，我们证明了 TGF-β 超家族信号通路成员 Smad3 和 BMPR2 之间在 VSMC 增殖中的功能串扰。Smad3 在 TGF-β/Smad3 信号通路中起重要作用，在再狭窄的颈动脉中显著上调，以促进 VSMC 增殖。相比之下，BMP 受体 II（BMPR2），一种 VSMC 增殖的抑制剂，在颈动脉再狭窄中下调。我们进一步发现，BMPR2 的下调是由 miR-17-92 簇介导的，该簇受 Smad3 转录调控。因此，Smad3 的上调和 Smad3/miR-17-92 簇依赖性 BMPR2 下调可能促进 VSMC 增殖和再狭窄。总之，我们的结果可能为颈动脉再狭窄的早期诊断和开发新的治疗策略提供新的线索。
