A novel role of CCN3 in regulating endothelial inflammation

Journal of Cell Communication and Signaling - Tập 4 - Trang 141-153 - 2010
Zhiyong Lin1, Viswanath Natesan1, Hong Shi1, Anne Hamik1, Daiji Kawanami1, Caili Hao1, Ganapati H. Mahabaleshwar1, Weiye Wang2, Zheng-Gen Jin2, G. Brandon Atkins1, Sue M. Firth3, Laure Rittié4, Bernard Perbal4,5,6, Mukesh K. Jain1
1University Hospitals Harrington-McLaughlin Heart & Vascular Institute and Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, USA
2Aab Cardiovascular Research Institute and Department of Medicine, Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, USA
3Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, Australia
4Department of Dermatology, University of Michigan, Ann Arbor, USA
5Laboratoire d’oncologie virale et moleculaire Université Paris, Paris, France
6L’Oreal R & D, Clark, USA

Tóm tắt

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.

Tài liệu tham khảo

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