Downregulation of Cavin-1 Expression via Increasing Caveolin-1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury-Induced Neointimal Hyperplasia.
Downregulation of Cavin-1 Expression via Increasing Caveolin-1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury-Induced Neointimal Hyperplasia.
复制标题
通过增加 Caveolin-1 降解来下调 Cavin-1 表达，可促进球囊损伤诱导的内膜增生中血管平滑肌细胞的增殖和迁移。
DOI：
10.1161/jaha.117.005754
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发表时间：
2017-07-27
影响因子：
5.4
通讯作者：
Tan Z
中科院分区：
文献类型：
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作者：
Zhou LJ;Chen XY;Liu SP;Zhang LL;Xu YN;Mu PW;Geng DF;Tan Z
经皮冠状动脉介入治疗已广泛应用于缺血性心脏病的治疗，但血管再狭窄是经皮冠状动脉介入治疗的主要限制因素。我们之前的工作报告称，小窝蛋白-1在内膜增生中发挥关键功能作用，而Cavin-1（另一种重要的小窝相关蛋白）是否参与其中尚不清楚。因此，我们将研究Cavin‐1对新生内膜形成的影响。球囊损伤显著降低Cavin-1蛋白表达，增加泛素蛋白表达，同时伴有损伤颈动脉新生内膜增生，而Cavin-1 mRNA无变化。在培养的血管平滑肌细胞（VSMCs）中，Cavin-1在放线菌酮抑制蛋白质合成后下调，蛋白酶体抑制剂MG 132预处理可明显阻止，但溶酶体抑制剂氯喹不能阻止，表明蛋白酶体降解导致Cavin-1下调。通过在体内球囊损伤的颈动脉中局部注射Cavin-1短发夹RNA（shRNA）来敲低Cavin-1可促进新生内膜形成。此外，体外培养的VSMC中Cavin-1的抑制或过表达分别通过增加或降低细胞外信号调节激酶磷酸化和基质降解金属蛋白酶-9活性来促进或抑制VSMC增殖和迁移。然而，在基础条件下，Cavin-1对VSMC迁移的影响强于对增殖的影响。此外，我们的结果表明Cavin-1通过溶酶体降解途径调节小窝蛋白-1的表达。我们的研究揭示了Cavin-1下调通过促进VSMC增殖、迁移和同步增强caveolin-1溶酶体降解在新生内膜形成中的作用和机制。Cavin-1可能是治疗损伤后血管重塑的潜在治疗靶点。
Percutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin‐1 had a key functional role in intimal hyperplasia, whereas whether Cavin‐1 (another important caveolae‐related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin‐1 on neointimal formation. Balloon injury markedly reduced Cavin‐1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin‐1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin‐1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin‐1 downregulation. Knockdown of Cavin‐1 by local injection of Cavin‐1 short hairpin RNA (shRNA) into balloon‐injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin‐1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal‐regulated kinase phosphorylation and matrix‐degrading metalloproteinases‐9 activity, respectively. However, under basic conditions, the effect of Cavin‐1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin‐1 regulated caveolin‐1 expression via lysosomal degradation pathway. Our study revealed the role and the mechanisms of Cavin‐1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin‐1 lysosomal degradation. Cavin‐1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.