Physicians' Academy for Cardiovascular Education

BET inhibitor downregulates components of complement cascade

Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208)

Wasiak S, Gilham D, Tsujikawa LM, et al. - J. of Cardiovasc. Trans. Res. 2017, In press

Background

Apabetalone (RVX-208) is an epigenetic regulator that affects transcription, thereby modulating pathways that underline cardiovascular disease (CVD), such as reverse cholesterol transport, vascular inflammation, coagulation and complement.

The complement system is an essential component of the innate immunity and a major initiator of host inflammatory responses. This system consists of more than 30 proteins, of which some are secreted into the bloodstream by hepatocytes and others associate with the plasma membrane of many other cell types. It can be activated through 3 distinct pathways: the classical, lectin and alternative pathway, each ending into the C5-driven pathway. These pathways can also be downregulated by multiple proteins. Complement expression and activity are tightly regulated to avoid immune dysregulation and host tissue damage [1]. Dysregulation is associated with increased susceptibility to infectious diseases and non-infectious disorders with an autoimmune and chronic inflammatory component, such as cardiometabolic disease including atherosclerosis, diabetes, metabolic syndrome and acute coronary syndrome [2].

RVX-208 is an orally available experimental small molecule that targets bromodomain and extraterminal (BET) proteins BRD2, BRD3 and BRD4, which regulate epigenetics. It is developed to treat CVD [3]. In contrast to the pan-BET inhibitors that preferably bind to BD1 and BD2 domains of BET proteins, RVX-208 rather binds to BD2 [4]. Post hoc analyses of pooled data from phase IIb SUSTAIN and ASSURRE trials showed that RVX-208 enhances HDL-c and ApoA-1, while lowering the incidence of MACE in CVD patients [5].

In this current study, the beneficial effects of RVX-208 beyond the improvement of the lipid profile were investigated. For this, in vitro experiments were performed using primary human hepatocytes or cell lines as well as in vivo experiments in urokinase-type plasminogen activator (uPA)/severe combined immunodeficient (SCID) mice with livers repopulated with human hepatocytes. Furthermore, proteomic analyses, including complement components, were performed using plasma from coronary artery disease (CAD) patients treated with 200 mg RVS-208 daily (n=77) or placebo (n=72) in the ASSERT and ASSURRE trials.

Main results

In vitro experiments

In vivo experiments

Patient plasma protein expression

Conclusion

BET inhibitor RVX-208 shows a repressive effect on expression of multiple complement cascade components and regulators. As these effects were also observed with a different BET inhibitor, JQ1, this seems to be BET inhibitor-specific rather than RVX-208-specific. This was also observed when complement was induced upon cytokine treatment. In vitro and in vivo experiments were confirmed with CAD patient analyses, which showed a reduction in circulating levels of multiple complement components and regulators with RVX-208, versus placebo. Thus, in addition to improving the lipoprotein and inflammatory profile, RVX-208 may benefit CVD patients by modulating the complement cascade.

References

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Find this article online at Journal of Cardiovascular Translational Research