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Author Notes:

Corresponding Author: Amir Rezvan, MD, MS, Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, 101 Woodruff Circle, WMRB Room 319A, Phone: 404-727-7011, Fax: 404-727-4397, amir.rezvan@emory.edu

Conflict of interest: The authors declare no conflict of interest.

Subject:

Research Funding:

This work was supported by funding from National Institutes of Health Grant HL124292 to AR, and HL095070 to HJ.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Pathology
  • Research & Experimental Medicine
  • CLASSICAL DENDRITIC CELLS
  • DISTURBED FLOW
  • FACTOR ZDC
  • STRESS
  • ATHEROSCLEROSIS
  • DYSFUNCTION
  • ACTIVATION
  • MECHANISMS
  • RESPONSES

ZBTB46 is a shear-sensitive transcription factor inhibiting endothelial cell proliferation via gene expression regulation of cell cycle proteins

Tools:

Journal Title:

Laboratory Investigation

Volume:

Volume 99, Number 3

Publisher:

, Pages 305-318

Type of Work:

Article | Post-print: After Peer Review

Abstract:

ZBTB46 is a transcription factor identified in classical dendritic cells and keeps dendritic cells in a quiescent state. Chromatin immunoprecipitation sequencing in dendritic cells has identified over 1300 potential gene targets of ZBTB46, affecting many processes including cell cycle. Endothelial cells (ECs) also express ZBTB46 and are mostly in a quiescent non-proliferative state. While EC proliferation is a critical process in development, dysregulation of EC proliferation as seen in areas of disturbed flow play an important role in many disease processes such as atherosclerosis, pulmonary hypertension, transplant vasculopathy, neointimal hyperplasia, and in-stent restenosis. We studied the role of ZBTB46 in ECs, hypothesizing that it inhibits EC proliferation. Using a model of disturbed flow in mice, we found that ZBTB46 is expressed in murine arterial ECs in vivo, and is downregulated by disturbed flow. In vitro results using HAECs showed that cell confluence and laminar shear stress, both known physiological conditions promoting EC quiescence, led to upregulation of ZBTB46 expression. Adenoviral-mediated overexpression of ZBTB46 in vitro caused reduced EC proliferation, and increased number of cells in the G 0 /G 1 phase of cell cycle, without affecting apoptosis or senescence, while siRNA knockdown of ZBTB46 negated the known inhibitory role of unidirectional laminar shear stress on EC proliferation. ZBTB46 overexpression also led to a broad suppression of genes involved in cell cycle progression including multiple cyclins and cyclin-dependent kinases, but an increase in the CDK inhibitor CDKN1A. Phosphorylation of the retinoblastoma protein was also decreased as assessed by Western blot. Tube formation on Matrigel was reduced, suggesting an inhibitory role for ZBTB46 in angiogenesis. Further research is required to investigate the potential role of ZBTB46 in specific pathologic conditions and whether it can be targeted in a therapeutic manner.

Copyright information:

© 2018, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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