Abstract 545: Suppression of Atherosclerosis by Synthetic REV-ERB Agonist

Abstract

Background: Development of atherosclerosis is a complex process that involves both hyperlipidemia and inflammation. Therapies that can target both metabolic and inflammatory aspect of this disease have significant potential in the treatment of cardiovascular diseases. The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in regulation of metabolism and inflammation. Recently it was demonstrated that knock-down of REV-ERBα in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. Methods and Results: A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Eight-week-old mice with deficient LDL receptor were fed high cholesterol diet and treated with vehicle or REV-ERB agonist, SR9009 (100mg/kg, I.P.) for a period of eight weeks. Atherosclerotic plaque size was significantly reduced in mice administered SR9009 compared to control mice. In another study plasma lipid levels were monitored every two weeks for eight weeks. We demonstrate that SR9009 significantly reduced plasma lipid levels in these mice. To determine the role of REV-ERB in macrophage differentiation and polarization bone-marrow derived macrophages (BMDM) were treated with SR9009 in vitro. SR9009 treatment of BMDM reduced the polarization of BMDM to proinflammatory M1 macrophage. Gene expression of markers of M1 polarization as well as pro-inflammatory cytokine secretion was reduced in macrophages treated with SR9009. Conclusions: We demonstrate that REV-ERB targets multiple processes involved in atherosclerosis. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis.