Apabetalone downregulates factors and pathways associated with vascular calcification.
Alkaline Phosphatase
/ metabolism
Binding Sites
Calcification, Physiologic
/ drug effects
Cardiovascular Diseases
/ genetics
Cell Cycle Proteins
/ metabolism
Cell Transdifferentiation
/ drug effects
Cells, Cultured
Computational Biology
Coronary Vessels
/ metabolism
Down-Regulation
Epigenesis, Genetic
Epigenomics
Humans
Muscle, Smooth, Vascular
/ cytology
Myocytes, Smooth Muscle
/ cytology
Protein Domains
Quinazolinones
/ pharmacology
RNA, Messenger
/ metabolism
Transcription Factors
/ metabolism
Vascular Calcification
/ drug therapy
Alkaline phosphatase
Apabetalone
Cardiovascular disease
Epigenetics
Transcription regulation
Vascular calcification
Journal
Atherosclerosis
ISSN: 1879-1484
Titre abrégé: Atherosclerosis
Pays: Ireland
ID NLM: 0242543
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
29
06
2018
revised:
28
09
2018
accepted:
07
11
2018
pubmed:
27
11
2018
medline:
25
3
2020
entrez:
27
11
2018
Statut:
ppublish
Résumé
Apabetalone is an inhibitor of bromodomain and extraterminal (BET) proteins. In clinical trials, apabetalone reduced the incidence of major adverse cardiac events (MACE) in patients with cardiovascular disease and reduced circulating factors that promote vascular calcification (VC). Because VC contributes to MACE, effects of apabetalone on pro-calcific processes were examined. Apabetalone inhibited extracellular calcium deposition and opposed induction of transdifferentiation markers in human coronary artery vascular smooth muscle cells (VSMCs) under osteogenic culture conditions. Tissue-nonspecific alkaline phosphatase (TNAP) is a key contributor to VC, and apabetalone suppressed osteogenic induction of the mRNA, protein and enzyme activity. The liver is a major source of circulating TNAP, and apabetalone also downregulated TNAP expression in primary human hepatocytes. BRD4, a transcriptional regulator and target of apabetalone, has been linked to calcification. Osteogenic transdifferentiation of VSMCs resulted in disassembly of 100 BRD4-rich enhancers, with concomitant enlargement of remaining enhancers. Apabetalone reduced the size of BRD4-rich enhancers, consistent with disrupting BRD4 association with chromatin. 38 genes were uniquely associated with BRD4-rich enhancers in osteogenic conditions; 11 were previously associated with calcification. Apabetalone reduced levels of BRD4 on many of these enhancers, which correlated with decreased expression of the associated gene. Bioinformatics revealed BRD4 may cooperate with 7 specific transcription factors to promote transdifferentiation and calcification. Apabetalone counters transdifferentiation and calcification of VSMCs via an epigenetic mechanism involving specific transcription factors. The mechanistic findings, combined with evidence from clinical trials, support further development of apabetalone as a therapeutic for VC.
Sections du résumé
BACKGROUND AND AIMS
Apabetalone is an inhibitor of bromodomain and extraterminal (BET) proteins. In clinical trials, apabetalone reduced the incidence of major adverse cardiac events (MACE) in patients with cardiovascular disease and reduced circulating factors that promote vascular calcification (VC). Because VC contributes to MACE, effects of apabetalone on pro-calcific processes were examined.
METHODS AND RESULTS
Apabetalone inhibited extracellular calcium deposition and opposed induction of transdifferentiation markers in human coronary artery vascular smooth muscle cells (VSMCs) under osteogenic culture conditions. Tissue-nonspecific alkaline phosphatase (TNAP) is a key contributor to VC, and apabetalone suppressed osteogenic induction of the mRNA, protein and enzyme activity. The liver is a major source of circulating TNAP, and apabetalone also downregulated TNAP expression in primary human hepatocytes. BRD4, a transcriptional regulator and target of apabetalone, has been linked to calcification. Osteogenic transdifferentiation of VSMCs resulted in disassembly of 100 BRD4-rich enhancers, with concomitant enlargement of remaining enhancers. Apabetalone reduced the size of BRD4-rich enhancers, consistent with disrupting BRD4 association with chromatin. 38 genes were uniquely associated with BRD4-rich enhancers in osteogenic conditions; 11 were previously associated with calcification. Apabetalone reduced levels of BRD4 on many of these enhancers, which correlated with decreased expression of the associated gene. Bioinformatics revealed BRD4 may cooperate with 7 specific transcription factors to promote transdifferentiation and calcification.
CONCLUSIONS
Apabetalone counters transdifferentiation and calcification of VSMCs via an epigenetic mechanism involving specific transcription factors. The mechanistic findings, combined with evidence from clinical trials, support further development of apabetalone as a therapeutic for VC.
Identifiants
pubmed: 30476723
pii: S0021-9150(18)31457-6
doi: 10.1016/j.atherosclerosis.2018.11.002
pii:
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Quinazolinones
0
RNA, Messenger
0
Transcription Factors
0
apabetalone
8R4A7GDZ1D
Alkaline Phosphatase
EC 3.1.3.1
Banques de données
ClinicalTrials.gov
['NCT02586155']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
75-84Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.