Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UMLS:C0004153 (
atherosclerosis
)
77,401
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:ZBTB46 is a shear-sensitive transcription factor inhibiting endothelial cell proliferation via gene expression regulation of cell cycle proteins. 2988 9
