CCN1 knockdown suppresses neointimal hyperplasia in a rat artery balloon injury model
CCN1 knockdown suppresses neointimal hyperplasia in a rat artery balloon injury model
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DOI：
10.1161/atvbaha.108.162362
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发表时间：
2008-06-01
影响因子：
8.7
通讯作者：
Tanaka, Makoto
中科院分区：
文献类型：
--
作者：
Matsumae, Hironobu;Yoshida, Yoshinori;Tanaka, Makoto
目的：CCN1(Cyr61)是一种细胞外基质相关蛋白，参与细胞增殖和存活。CCN1通过整合素与血管平滑肌细胞(VSMCs)结合，并在动脉粥样硬化病变的VSMCs中表达，提示CCN1参与了血管平滑肌细胞(VSMC)增殖和动脉粥样硬化的调节。我们假设CCN1基因的敲除可能抑制VSMC的增殖和抑制新生内膜的增殖。方法和结果-我们通过大鼠培养的VSMC和大鼠球囊损伤模型检测了CCN1基因敲除的效果。CCN1以剂量依赖的方式刺激VSMCs的黏附和迁移，这一作用可被整合素α(6)β(1)抗体阻断。此外，慢病毒介导的siRNA抑制内源性CCN1表达可显著抑制VSMCs的增殖和5-溴-2‘-脱氧尿苷(BrdU)的摄取。补充重组CCN1可逆转siRNA敲除的作用。有趣的是，在大鼠颈动脉球囊损伤模型中，在损伤后第14天和第28天，CCN1的敲除显著抑制了新生内膜的增殖。将CCN1基因转移到血管内皮细胞可逆转CCN1基因敲除对新生内膜形成的影响。结论抑制CCN1可能为预防血管介入术后再狭窄提供了一种有前景的策略。
Objective-CCN1 (Cyr61) is an extracellular matrix-associated protein involved in cell proliferation and survival. CCN1 is bound to vascular smooth muscle cells (VSMCs) via integrins and is expressed in VSMCs in atherosclerotic lesions, suggesting involvement in the regulation of vascular smooth muscle cell (VSMC) proliferation and atherosclerosis. We hypothesized that knockdown of CCN1 may inhibit VSMC proliferation and suppress neointimal hyperplasia.Methods and Results-We examined the effect of the knockdown of CCN1 using rat cultured VSMCs and a rat balloon injury model. CCN1 stimulated adhesion and migration of VSMCs in a dose-dependent manner, and this was blocked by an antibody for integrin alpha(6)beta(1). Moreover, knockdown of endogenous CCN1 by lentiviral delivery of siRNA significantly inhibited proliferation of VSMCs and the uptake of 5-bromo-2'-deoxyuridine (BrdU). Replenishment with recombinant CCN1 reversed the effect of siRNA knockdown. Interestingly, knockdown of CCN1 significantly suppressed neointimal hyperplasia in a rat carotid artery balloon injury model at days 14 and 28 after injury. Gene transfer of CCN1 to smooth muscle reversed the effect of CCN1 knockdown on neointimal formation. These results suggest that endogenous CCN1 regulates proliferation of VSMCs and neointimal hyperplasia.Conclusion-Inhibition of CCN1 may provide a promising strategy for the prevention of restenosis after vascular interventions.