1. Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208)
- Author
-
Cyrus Calosing, Laura Tsujikawa, Ewelina Kulikowski, Jan Johansson, Sylwia Wasiak, Michael O. Sweeney, Dean Gilham, Norman C.W. Wong, Christopher Halliday, and Ravi Jahagirdar
- Subjects
0301 basic medicine ,Proteomics ,Pharmaceutical Science ,Bromodomain ,Mice, SCID ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,0302 clinical medicine ,Transcriptional regulation ,Complement Activation ,Genetics (clinical) ,Cells, Cultured ,Innate immunity ,Reverse cholesterol transport ,Complement cascade ,Cardiovascular Diseases ,Molecular Medicine ,Cytokines ,Original Article ,Epigenetics ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,Primary Cell Culture ,Inflammation ,RVX 208 ,Biology ,Bromodomain and extraterminal protein ,03 medical and health sciences ,Downregulation and upregulation ,Genetics ,medicine ,Animals ,Humans ,Quinazolinones ,Innate immune system ,Gene Expression Profiling ,Proteins ,Biomarker ,Complement System Proteins ,Cardiovascular disease ,major acute cardiac event ,Immunity, Innate ,Complement system ,030104 developmental biology ,Complement Inactivating Agents ,chemistry ,Immunology ,Cancer research ,Hepatocytes ,Quinazolines - Abstract
Apabetalone (RVX-208) is an epigenetic regulator developed to treat cardiovascular disease (CVD) that targets BET proteins. Through transcriptional regulation RVX-208 modulates pathways that underlie CVD including reverse cholesterol transport, vascular inflammation, coagulation, and complement. Using transcriptomics and proteomics we show that complement is one of the top pathways downregulated by RVX-208 in primary human hepatocytes (PHH) and in plasma from CVD patients. RVX-208 reduces basal and cytokine-driven expression of complement factors in PHH and in chimeric mice with humanized livers. Plasma proteomics of CVD patients shows that RVX-208 decreases complement proteins and regulators, including complement activators SAP and CRP. Circulating activated fragments C5a, C3b, and C5b-C6 are reduced by 51, 32, and 10%, respectively, indicating decreased activity of complement in patients. As complement components are linked to CVD and metabolic syndrome, including major acute cardiac events, modulating their levels and activity by RVX-208 may alleviate risks associated with these diseases. Electronic supplementary material The online version of this article (doi:10.1007/s12265-017-9755-z) contains supplementary material, which is available to authorized users.
- Published
- 2017