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.

中文翻译：

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在小鼠和患有心血管疾病的患者中，阿帕贝单抗的表观遗传调控可对抗细胞因子驱动的急性期反应。

慢性全身性炎症会导致心血管疾病（CVD），并与肝脏和血浆中大量的急性期反应（APR）蛋白相关。Bromodomain和Extraterminal（BET）蛋白是调节炎症基因转录的表观遗传阅读器。我们显示，小分子阿帕贝酮对BET的抑制作用可降低APR基因和人肝细胞，小鼠模型和CVD患者血浆中的蛋白质表达。在培养的肝细胞和人源化小鼠肝脏中，阿帕贝酮可降低血清淀粉样蛋白P，纤溶酶原激活物抑制剂1和铜蓝蛋白（与CVD风险相关的APR蛋白）的稳态表达。在细胞因子刺激的肝细胞中，阿帕贝龙降低C反应蛋白（CRP），α-2-巨球蛋白和血清淀粉样蛋白P的表达。内毒素血症小鼠肝脏中的apabetalone也可降低后两者的毒性。BET淘汰赛体外还对抗细胞因子介导的CRP基因诱导。从机理上讲，apabetalone降低了CRP启动子上细胞因子驱动的BRD4 BET占有率的增加，证实CRP的转录是BET依赖性的。在具有稳定冠心病的患者中，与安慰剂相比，apabetalone治疗后血浆APR蛋白CRP，IL-1受体拮抗剂和血纤蛋白原γ降低，从而导致APR途径和细胞因子靶标的预期下调。我们得出的结论是，CRP和APR途径的组成部分受BET蛋白的调节，并且apabetalone可以对抗患者的慢性细胞因子信号传导。