title: Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE(-/-) mice.
abstract: OBJECTIVE
  Our previous in vitro and clinical work has demonstrated anti-inflammatory effects of berberine (BBR), but the clinical application of BBR is limited by its poor bioavailability. Derivatives of BBR have been suggested to have enhanced bioavailability compared to BBR. In this study, we tested whether BBR derivatives, compared with BBR, had superior beneficial effects on atherosclerotic plaques in apoE(-/-) mice, and defined possible molecular mechanisms underlying such effects.
  
  
  METHODS
  Macrophages were pretreated with BBR and its derivatives, dihydroberberine (dhBBR) and 8,8-dimethyldihydroberberine (Di-MeBBR), before incubation with oxLDL. Cell surface EMMPRIN expression was measured by flow cytometry and Western blotting, and phospho-(p)-p38, p-JNK, nuclear NFκB p65, and phospho-p65 were measured by Western blotting. ApoE-/- mice fed with the Western diet for 16 weeks were treated with BBR, dhBBR and Di-MeBBR 16 weeks. Aortic atherosclerotic lesion size, plaque matrix proteins, and EMMPRIN and other inflammatory factors were measured using Oil Red O Staining, Masson's trichromestaining and immunohistochemical staining and real-time PCR.
  
  
  RESULTS
  Compared with BBR, dhBBR and Di-MeBBR significantly reduced EMMPRIN expression, which was associated with a greater inhibition of p-p38, p-JNK, nuclear NFκB p65 and phospho-p65 induced by oxLDL in macrophages. dhBBR and Di-MeBBR, but not BBR, reduced atherosclerotic plaque size and improved plaque stability indicated by increased α-smooth muscle actin and collagen content, and thicker fibrous caps. dhBBR and Di-MeBBR reduced expression of EMMPRIN, CD68, and NFκB p65, and Di-MeBBR also reduced expression of matrix metalloproteinase-9, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in aortic plaques.
  
  
  CONCLUSIONS
  These results have demonstrated that BBR derivatives, dhBBR and Di-MeBBR, are superior to BBR in inhibiting inflammation and reducing plaque size and vulnerability.
authors.affiliation: Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China. chonman_5@sina.com.
authors.forename: Junwen
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Shanghai Ninth People's Hospital Affiliated Shanghai Jiaotong University, School of Medicine, Shanghai, China. 65248500@qq.com.
authors.forename: Jiatian
authors.initials: J
authors.lastname: Cao
authors.affiliation: Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. fanglu99@hotmail.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China. liuboxinhua@qq.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China. kingzhou_78@126.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China. sunyinggang@gmail.com.
authors.forename: Yinggang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Shanghai Ninth People's Hospital Affiliated Shanghai Jiaotong University, School of Medicine, Shanghai, China. 724485569@qq.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China. drliyigang@outlook.com.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China. msdoctor@126.com.
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000517:prevention & control*; D001599:Berberine / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D001599:Berberine