Abstract
BackgroundPatients 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.ResultsMonocytes 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.ConclusionsMonocytes 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.
Highlights
Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event
We have demonstrated that monocytes isolated from Type 2 diabetes mellitus (DM2) + CVD patients exhibit a hyper-inflammatory phenotype at baseline and a hyper-responsiveness to inflammatory stimuli ex vivo
This activated monocyte state may contribute to the initiation and progression of atherosclerosis and increased cardiovascular risk in these patients
Summary
Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Wasiak et al Clin Epigenet (2020) 12:166 mellitus (DM2) is recognized as a contributor to CVD risk [1] This comorbidity is likely caused by organ exposure to chronic systemic low-grade inflammation caused by elevated circulating levels of cytokines IL-6 and IL-1β, glucose, free fatty acids and reactive oxygen species (ROS) [2,3,4,5,6]. Such a microenvironment favours monocyte infiltration into the arterial wall, where these cells differentiate into macrophages that contribute to initiation and progression of atherosclerosis. Macrophage activity in atherosclerotic plaque precipitates atherothrombosis and clinical cardiovascular events [7]
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