PloS one, 2013-12, Vol.8 (12), p.e83190
2013
Details
- Autor(en) / Beteiligte
- Titel
- RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist
- Ist Teil von
- PloS one, 2013-12, Vol.8 (12), p.e83190
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0083190Titel-ID: cdi_plos_journals_1473341847
- Format
- –
- Schlagworte
- Animals, Apolipoprotein A, Apolipoprotein A-I, Apolipoprotein A-I - biosynthesis, Apolipoprotein A-I - genetics, Arteriosclerosis, Atherosclerosis, Atherosclerosis - drug therapy, Atherosclerosis - metabolism, Binding Sites, Biology, Cardiovascular disease, Cell cycle, Cell Cycle Proteins, Cell Line, Cholesterol, Clinical trials, Collaboration, Crystallography, Crystallography, X-Ray, Cytokines, Epigenesis, Genetic - drug effects, Epigenetic inheritance, Epigenetics, Hepatocytes, Hepatocytes - drug effects, Hepatocytes - metabolism, High density lipoprotein, Humans, Lysine, Models, Molecular, Monkeys, mRNA, Nuclear Proteins - antagonists & inhibitors, Nuclear Proteins - chemistry, Nuclear Proteins - genetics, Pharmaceuticals, Pharmacology, Protein Conformation, Protein-Serine-Threonine Kinases - antagonists & inhibitors, Protein-Serine-Threonine Kinases - chemistry, Protein-Serine-Threonine Kinases - genetics, Proteins, Quinazolines - chemistry, Quinazolines - pharmacology, Quinazolinones, Recombinant Proteins - chemistry, Recombinant Proteins - genetics, RNA, RNA, Small Interfering - genetics, Signal transduction, siRNA, Studies, Systematic review, Transcription Factors - antagonists & inhibitors, Transcription Factors - chemistry, Transcription Factors - genetics, X-ray crystallography