| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Wasiak, Sylwia Dzobo, Kim E. Rakai, Brooke D. Kaiser, Yannick Versloot, Miranda Bahjat, Mahnoush Stotz, Stephanie C. Fu, Li Sweeney, Michael Johansson, Jan O. Wong, Norman C. W. Stroes, Erik S. G. Kroon, Jeffrey Kulikowski, Ewelina |
| Abstract | Background 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. |
| Related Links | https://clinicalepigeneticsjournal.biomedcentral.com/counter/pdf/10.1186/s13148-020-00943-0.pdf |
| Ending Page | 19 |
| Page Count | 19 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 18687083 |
| DOI | 10.1186/s13148-020-00943-0 |
| Journal | Clinical Epigenetics |
| Issue Number | 1 |
| Volume Number | 12 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2020-11-11 |
| Access Restriction | Open |
| Subject Keyword | Human Genetics Gene Function Bromodomain Transcription regulation Innate immune response Cardiovascular Apabetalone |
| Content Type | Text |
| Resource Type | Article |
| Subject | Molecular Biology Genetics (clinical) Developmental Biology Genetics |
| Journal Impact Factor | 4.8/2023 |
| 5-Year Journal Impact Factor | 5.8/2023 |
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