title: Suppression of atherosclerosis by synthetic REV-ERB agonist.
abstract: The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression 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. 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. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis.
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Sadichha
authors: S
authors: Sitaula
authors: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: Cyrielle
authors: C
authors: Billon
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Theodore M
authors: TM
authors: Kamenecka
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Laura A
authors: LA
authors: Solt
authors: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: burristp@slu.edu.
authors: Thomas P
authors: TP
authors: Burris
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D001483:Base Sequence; D017931:DNA Primers; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000819:agonists*; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology
chemical_list: D017931:DNA Primers; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011973:Receptors, LDL
keywords: Atherosclerosis; Macrophages; Nuclear receptor; REV-ERB