BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with
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RESEARCH
BET protein inhibitor apabetalone (RVX‑208) suppresses pro‑inflammatory hyper‑activation of monocytes from patients with cardiovascular disease and type 2 diabetes Sylwia Wasiak1†, Kim E. Dzobo2, Brooke D. Rakai1, Yannick Kaiser3, Miranda Versloot2, Mahnoush Bahjat2, Stephanie C. Stotz1, Li Fu1, Michael Sweeney1, Jan O. Johansson1, Norman C. W. Wong1, Erik S. G. Stroes3, Jeffrey Kroon2† and Ewelina Kulikowski1*†
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 Tolllike 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 20-fold higher affinity) [31–33], countering BET protein recruitment to chromatin. Consequently, apabetalone inhibits transcription of BET-dependent genes [31, 34]. In vitro treatment with apabetalone reduces pro-inflammatory gene expression in cellular models of atherosclerosis, including endothelial cells [34, 35], monocytes [34] and vascular smooth muscle cells [36]. Apabetalone also reduces vascular inflammation and atherosclerosis in mouse models [23, 35]. These data suggest that apabetalone could correct the pro-inflammatory phenotype of innate immune cells characteristic of DM2 and CVD. Here, we demonstrate that monocytes isolated from patients with DM2 and CVD (DM2 + CVD) have an enhanced pro-inflammatory phenotype as compared to matched controls. Moreover, challenging DM2 + CVD monocytes ex vivo with interferon gamma (IFNγ), a key cytokine that triggers monocyte differentiation into the pro-inflammatory macrophage M1 subtype [37], provokes a hyperactive transcriptional response as compared to controls. Ex vivo apabetalone treatment diminishes this hyper-inflammatory state, suggesting that BET protein inhibition can mitigate monocyte-driven inflammation in patients with high residual risk for major adverse cardiovascular events.
Results Apabetalone suppresses pro‑inflammatory cytokine secretion in monocytes from DM2 + CVD patients
For this study, we recr
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