In:
Clinical Epigenetics, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2020-12)
Abstract:
Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Dysregulation of epigenetic mechanisms of gene transcription in innate immune cells contributes to CVD development but is currently not targeted by therapies. Apabetalone (RVX-208) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins—histone acetylation readers that drive pro-inflammatory and pro-atherosclerotic gene transcription. Here, we assess the impact of apabetalone on ex vivo inflammatory responses of monocytes from DM2 + CVD patients. Results Monocytes isolated from DM2 + CVD patients and matched controls were treated ex vivo with apabetalone, interferon γ (IFNγ), IFNγ + apabetalone or vehicle and phenotyped for gene expression and protein secretion. Unstimulated DM2 + CVD monocytes had higher baseline IL-1α, IL-1β and IL-8 cytokine gene expression and Toll-like receptor (TLR) 2 surface abundance than control monocytes, indicating pro-inflammatory activation. Further, DM2 + CVD monocytes were hyper-responsive to stimulation with IFNγ, upregulating genes within cytokine and NF-κB pathways 〉 30% more than control monocytes ( p 〈 0.05). Ex vivo apabetalone treatment countered cytokine secretion by DM2 + CVD monocytes at baseline (GROα and IL-8) and during IFNγ stimulation (IL-1β and TNFα). Apabetalone abolished pro-inflammatory hyper-activation by reducing TLR and cytokine gene signatures more robustly in DM2 + CVD versus control monocytes. Conclusions Monocytes isolated from DM2 + CVD patients receiving standard of care therapies are in a hyper-inflammatory state and hyperactive upon IFNγ stimulation. Apabetalone treatment diminishes this pro-inflammatory phenotype, providing mechanistic insight into how BET protein inhibition may reduce CVD risk in DM2 patients.
Type of Medium:
Online Resource
ISSN:
1868-7075
,
1868-7083
DOI:
10.1186/s13148-020-00943-0
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2553921-8
