FP294INHIBITION OF BET PROTEINS WITH APABETALONE REDUCES MEDIATORS OF VASCULAR CALCIFICATION IN VITRO AND IN CKD PATIENTS
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".