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A novel role of CCN3 in regulating endothelial inflammation

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Journal of Cell Communication and Signaling Aims and scope

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.

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Abbreviations

CCN:

Cyr61, Ctgf, Nov

CCN3/NOV:

Nephroblastoma overexpressed

CCN1/Cyr61:

Cysteine-rich protein 61

CCN2/Ctgf:

Connective tissue growth factor

KLF:

Kruppel-like factor

HUVEC:

Human umbilical vein endothelial cells

VCAM-1:

Vascular adhesion molecule-1

NF-κB:

Nuclear Factor Kappa B

EC:

Endothelial cell

TNFα:

Tumor necrosis factor- α

IL-1β:

Interleulin-1 β

EBM:

Endothelial basal medium

GFP:

Green fluorescent protein

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Funding

This work was supported by NIH grants HL72952, HL75427, HL76754, HL086548, HL084154, and P01 HL48743 (to M.K.J.); HL087595 (to Z.L.); and HL088740 (to G.B.A.); and HL083090 (to A.H.) and a Robert Wood Johnson/Harold Amos Medical Faculty Development grant (to G.B.A.) and American Heart Association grants 0635579 T (to Z.L.) and 0725297B (to D.K.). BP was supported by the Ministere de la Recherche et de la Technologie (France), and acknowledges Professor G. Fisher (Ann Arbor- University of Michigan) for hosting.

Conflict of interest

none declared.

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Author notes

  1. Bernard Perbal

    Present address: L’Oreal R & D, Clark, NJ, 07066, USA

Authors and Affiliations

  1. University Hospitals Harrington-McLaughlin Heart & Vascular Institute and Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Wolstein Research Building, 2103 Cornell Road, Room 4-537, Cleveland, OH, 44106-7290, USA

    Zhiyong Lin, Viswanath Natesan, Hong Shi, Anne Hamik, Daiji Kawanami, Caili Hao, Ganapati H. Mahabaleshwar, G. Brandon Atkins & Mukesh K. Jain

  2. Aab Cardiovascular Research Institute and Department of Medicine, Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Weiye Wang & Zheng-Gen Jin

  3. Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, 2065, Australia

    Sue M. Firth

  4. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA

    Laure Rittié & Bernard Perbal

  5. Laboratoire d’oncologie virale et moleculaire Université Paris, 7-D. Diderot, Paris, France

    Bernard Perbal

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  1. Zhiyong Lin
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Correspondence to Zhiyong Lin or Mukesh K. Jain.

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Lin, Z., Natesan, V., Shi, H. et al. A novel role of CCN3 in regulating endothelial inflammation. J. Cell Commun. Signal. 4, 141–153 (2010). https://doi.org/10.1007/s12079-010-0095-x

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