Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease
Open Access
- 1 August 2020
- journal article
- research article
- Published by Hindawi Limited in Cardiovascular Therapeutics
- Vol. 2020, 1-12
- https://doi.org/10.1155/2020/9397109
Abstract
Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.Keywords
Funding Information
- Resverlogix Corp
This publication has 44 references indexed in Scilit:
- Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loadingNature Communications, 2017
- Immune disease-associated variants in gene enhancers point to BET epigenetic mechanisms for therapeutic interventionEpigenomics, 2017
- Functions of bromodomain-containing proteins and their roles in homeostasis and cancerNature Reviews Molecular Cell Biology, 2017
- Targeting bromodomains: epigenetic readers of lysine acetylationNature Reviews Drug Discovery, 2014
- RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain AntagonistPLOS ONE, 2013
- RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomainProceedings of the National Academy of Sciences of the United States of America, 2013
- Hepatic acute phase proteins – Regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signalingEuropean Journal of Cell Biology, 2012
- Regulatory Mechanisms Controlling Inflammation and Synthesis of Acute Phase ProteinsPublished by IntechOpen ,2011
- Recruitment of P-TEFb for Stimulation of Transcriptional Elongation by the Bromodomain Protein Brd4Molecular Cell, 2005
- The Bromodomain Protein Brd4 Is a Positive Regulatory Component of P-TEFb and Stimulates RNA Polymerase II-Dependent TranscriptionMolecular Cell, 2005