A novel role of CCN3 in regulating endothelial inflammation

Zhiyong Lin, Viswanath Natesan, Hong Shi, Anne Hamik, Daiji Kawanami, Caili Hao, Ganapati H. Mahabaleshwar, Weiye Wang, Zheng Gen Jin, G. Brandon Atkins, Sue M. Firth, Laure Rittié, Bernard Perbal, Mukesh K. Jain

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)141-153
Number of pages13
JournalJournal of Cell Communication and Signaling
Volume4
Issue number3
DOIs
StatePublished - Oct 2010
Externally publishedYes

Keywords

  • CCN3
  • Endothelium
  • Inflammation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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