J Cell Commun Signal. 2010 Oct;4(3):141-53. doi: 10.1007/s12079-010-0095-x. Epub 2010 Aug 11.
The vascular endothelium plays a fundamental role in the health and disease of the cardiovascular system. The molecular mechanisms regulating endothelial homeostasis, however, remain incompletely understood. CCN3, a member of the CCN (Cyr61, Ctgf, Nov) family of cell growth and differentiation regulators, has been shown to play an important role in numerous cell types. The function of CCN3 in endothelial cells has yet to be elucidated. Immunohistochemical analysis of CCN3 expression in mouse tissues revealed robust immunoreactivity in the endothelium of large arteries, small resistance vessels, and veins. We found that CCN3 expression in human umbilical vein endothelial cells (HUVECs) is transcriptionally induced by laminar shear stress (LSS) and HMG CoA-reductase inhibitors (statins). Promoter analyses identified the transcription factor Kruppel-like factor 2 (KLF2) as a direct regulator of CCN3 expression. In contrast to LSS, proinflammatory cytokines reduced CCN3 expression. Adenoviral overexpression of CCN3 in HUVEC markedly inhibited the cytokine-mediated induction of vascular adhesion molecule-1 (VCAM-1). Consistent with this observation, CCN3 significantly reduced monocyte adhesion. Conversely, CCN3 knockdown in HUVECs resulted in enhancement of cytokine-induced VCAM-1 expression. Concordant effects were observed on monocyte adhesion. Gain and loss-of-function mechanistic studies demonstrated that CCN3 negatively regulates nuclear factor kappaB (NF-κB) activity by reducing its translocation into the nucleus and subsequent binding to the VCAM-1 promoter, suggesting that CCN3's anti-inflammatory effects occur secondary to inhibition of NF-κB nuclear accumulation. This study identifies CCN3 as a novel regulator of endothelial proinflammatory activation.
血管内皮细胞在心血管系统的健康和疾病中起着至关重要的作用。然而，调节内皮细胞稳态的分子机制仍不完全清楚。CCN3 是细胞生长和分化调节剂 CCN（Cyr61、Ctgf、Nov）家族的成员，它在许多细胞类型中发挥着重要作用。CCN3 在血管内皮细胞中的功能尚未阐明。对小鼠组织中 CCN3 表达的免疫组织化学分析显示，在大动脉、小阻力血管和静脉的内皮细胞中存在强烈的免疫反应性。我们发现，层流剪切力（LSS）和 HMG CoA 还原酶抑制剂（他汀类药物）可诱导人脐静脉内皮细胞（HUVEC）中 CCN3 的转录表达。启动子分析确定转录因子 Kruppel 样因子 2（KLF2）是 CCN3 表达的直接调节因子。与 LSS 相反，促炎细胞因子降低了 CCN3 的表达。HUVEC 中 CCN3 的腺病毒过表达显著抑制了细胞因子介导的血管细胞黏附分子-1（VCAM-1）的诱导。与这一观察结果一致，CCN3 显著减少了单核细胞黏附。相反，HUVEC 中的 CCN3 敲低导致细胞因子诱导的 VCAM-1 表达增强。单核细胞黏附也观察到了一致的效果。获得和丧失功能的机制研究表明，CCN3 通过减少核易位及其与 VCAM-1 启动子的结合来负调控核因子 kappaB（NF-κB）活性，表明 CCN3 的抗炎作用继发于 NF-κB 核积累的抑制。本研究确定 CCN3 是内皮细胞促炎激活的一种新的调节因子。
