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Journal of Translational Medicine

, 12:326

Cardiovascular, Metabolic and Lipoprotein Translation

Abstract

Background and aimsOur 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.

MethodsMacrophages 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.

ResultsCompared 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.

ConclusionsThese results have demonstrated that BBR derivatives, dhBBR and Di-MeBBR, are superior to BBR in inhibiting inflammation and reducing plaque size and vulnerability.

KeywordsBerberine derivatives EMMPRIN Inflammation Atherosclerosis Plaque stability AbbreviationsACSAcute coronary syndrome

α-SMAα-smooth muscle actin

BBRBerberine

dhBBRDihdroberberine

Di-MeBBR8,8-dimethyldihydroberberine

EMMPRINExtracellular matrix metalloproteinase inducer

HDL-CHigh-density lipoprotein cholesterol

ICAM-1Intercellular adhesion molecule-1

LDL-CLow-density lipoprotein cholesterol

MAPKMitogen-activated protein kinase

MMPsMetalloproteinases

NFκBNuclear factor-κB

TCTotal cholesterol

TGTotal triglycerides

VCAM-1Vascular cell adhesion molecule-1

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-014-0326-7 contains supplementary material, which is available to authorized users.

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Autor: Junwen Chen - Jiatian Cao - Lu Fang - Bo Liu - Qing Zhou - Yinggang Sun - Yue Wang - Yigang Li - Shu Meng

Fuente: https://link.springer.com/







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