rvx-208 and Endotoxemia

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

Topics: alpha-Macroglobulins; Animals; Anti-Inflammatory Agents; Binding Sites; C-Reactive Protein; Cardiovascular Diseases; Cells, Cultured; Ceruloplasmin; Cytokines; Disease Models, Animal; Endotoxemia; Epigenesis, Genetic; Hepatocytes; Male; Mice, Inbred C57BL; Nuclear Proteins; Plasminogen Activator Inhibitor 1; Promoter Regions, Genetic; Quinazolinones; Serum Amyloid P-Component; Signal Transduction; Transcription Factors