FP294INHIBITION OF BET PROTEINS WITH APABETALONE REDUCES MEDIATORS OF VASCULAR CALCIFICATION IN VITRO AND IN CKD PATIENTS
Notice bibliographique
Résumé
INTRODUCTION AND AIMS: Bromodomain and extraterminal (BET) proteins, such as BRD4, modulate gene expression by bridging acetylated histones & transcription factors with transcriptional regulators. Apabetalone, an orally active BET inhibitor, reduced the incidence of major adverse cardiac events (MACE) in patients with CVD and improved eGFR in a subpopulation with chronic kidney disease (CKD) in phase 2 trials. In CKD patients, vascular calcification (VC) increases CVD risk & is a predictor of all-cause mortality. Because VC is associated with MACE, effects of BET inhibition on processes associated with VC were examined. METHODS: Proteomic profiling of plasma was conducted in CVD patients receiving apabetalone in the 3 month (ASSERT) and 6 month (SUSTAIN & ASSURE) phase 2 trials, as well as in patients with stage 4/5 CKD receiving a single dose in a phase 1 pharmacokinetic study. Human coronary artery vascular smooth muscle cells (VSMCs) were used to assess expression of VC markers, trans-differentiation in osteogenic conditions, and extracellular mineralization that leads to pathology. ChIP-seq examined BRD4 assembly on chromatin during osteogenic trans-differentiation and the effects of apabetalone. RESULTS: Apabetalone reduced circulating levels of proteins associated with VC in phase 2 trials in CVD patients including osteopontin, osteoprotegerin (OPG), & alkaline phosphatase (ALP). Proteomic assessment of plasma from CKD patients vs matched controls demonstrated activation of molecular pathways driving VC including BMP-2 signaling and RANK signaling in osteoclasts. Both pathways were downregulated by apabetalone 12 hours post dose in the CKD cohort. Mechanistic effects of apabetalone were examined in vitro. Trans-differentiation of VSMCs with osteogenic conditions induced expression of ALP, OPG, RUNX2 & WNT5A, which was suppressed by apabetalone. Further, apabetalone dose dependently countered extracellular calcium deposition. Compared to basal conditions, trans-differentiation to a calcifying phenotype promoted re-distribution of BRD4 on chromatin, resulting in fewer enhancers (118 in osteogenic, 288 in basal). 38 unique enhancers were generated in osteogenic conditions, several of which were in proximity to genes associated with calcification. Apabetalone dose dependently reduced levels of BRD4 on many of these enhancers, which correlated with decreased expression of the associated gene. Genome wide, apabetalone decreased the size of BRD4 containing enhancers, consistent with its mechanism of action. CONCLUSIONS: In clinical trials, apabetalone mediates reduction of factors & pathways associated with VC. Involvement of BRD4 in VSMC trans-differentiation & calcification is a novel discovery. BRD4 ChIP-seq identified novel factors associated with trans-differentiation, and thus potential targets to oppose VC. Inhibition of BRD4 by apabetalone resulted in fewer BRD4 containing enhancers, and reduced expression of genes that promote (a) trans-differentiation & (b) extracellular calcium deposition. The impact of chronic treatment with apabetalone on biomarkers, renal function and CVD outcomes in patients with impaired kidney function is being studied in the phase 3 BETonMACE outcomes trial.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».