Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease
Joint Authors
Wasiak, Sylwia
Gilham, Dean
Daze, Emily
Tsujikawa, Laura M.
Halliday, Christopher
Stotz, Stephanie C.
Rakai, Brooke D.
Fu, Li
Jahagirdar, Ravi
Sweeney, Michael
Johansson, Jan O.
Wong, Norman C. W.
Kulikowski, Ewelina
Source
Issue
Vol. 2020, Issue 2020 (31 Dec. 2020), pp.1-12, 12 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2020-08-01
Country of Publication
Egypt
No. of Pages
12
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Tsujikawa, Laura M.& Halliday, Christopher& Stotz, Stephanie C.& Rakai, Brooke D.& Fu, Li& Jahagirdar, Ravi…[et al.]. 2020. Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease. Cardiovascular Therapeutics،Vol. 2020, no. 2020, pp.1-12.
https://search.emarefa.net/detail/BIM-1138648
Modern Language Association (MLA)
Tsujikawa, Laura M.…[et al.]. Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease. Cardiovascular Therapeutics No. 2020 (2020), pp.1-12.
https://search.emarefa.net/detail/BIM-1138648
American Medical Association (AMA)
Tsujikawa, Laura M.& Halliday, Christopher& Stotz, Stephanie C.& Rakai, Brooke D.& Fu, Li& Jahagirdar, Ravi…[et al.]. Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease. Cardiovascular Therapeutics. 2020. Vol. 2020, no. 2020, pp.1-12.
https://search.emarefa.net/detail/BIM-1138648
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1138648