Abstract 671: Hepatic Expression of C-Reactive Protein is Epigenetically Regulated by BET Proteins and Inhibited by Apabetalone (RVX-208) <i>in vitro</i> and in CVD Patients
Bibliographic record
Abstract
Chronic inflammation contributes to cardiovascular disease (CVD) and is characterized by elevated plasma levels of interleukin (IL)-6, IL-1β and C-reactive protein (CRP). CRP serves as a CVD stratification marker as it correlates with major adverse cardiac events (MACE). Here we show that hepatic induction of CRP in response to chronic cytokine signaling is regulated by epigenetic mechanisms in vitro and in patients. Apabetalone is a small molecule inhibitor of epigenetic readers called bromodomain and extraterminal (BET) proteins that bind to acetylated DNA-associated proteins to regulate inflammatory gene transcription. In vitro, apabetalone attenuated CRP gene and protein expression under basal conditions in cultured primary human hepatocytes (PHH). Moreover, IL-6 and IL-1β mediated induction of CRP expression was also suppressed by apabetalone in both PHH and the HepaRG hepatic cell line (>50%). In HepaRG, PROTAC MZ-1 targeted degradation of BET proteins also reduced cytokine mediated CRP expression (93%), demonstrating that inflammatory expression of CRP is BET-dependent. Short-term cytokine treatment increased occupancy of the BET family member BRD4 on the CRP promoter, which was countered by either apabetalone or a structurally unrelated BET inhibitor JQ1. These data directly link BRD4 to CRP transcription. In a pooled analysis of phase 2 trials ASSERT, SUSTAIN and ASSURE, treatment with apabetalone resulted in a 62% relative risk reduction in MACE in CVD patients with elevated CRP (>2mg/L). In both ASSERT (12 weeks; n=55) and ASSURE (26 weeks; n=94), a comparison of baseline and end-of-study plasma proteome (SOMAscan 1.3K platform) detected a downregulation of inflammatory mediators, including CRP, in apabetalone treated patients versus placebo. Consequently, Ingenuity®-powered bioinformatics analysis of the proteomics data predicted an apabetalone-driven downregulation of inflammatory pathways. Based on this data, we predict that apabetalone reduces CVD associated chronic inflammation, contributing to the reduction in MACE in patients with high residual CVD risk. This is currently being explored in the phase 3 cardiovascular outcomes trial BETonMACE enrolling patients with CVD, type 2 diabetes mellitus and low HDL-c.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".