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.
Highlights
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
We further demonstrated that BBR treatment for 30 days, as an adjunct therapy, reduced serum levels of matrix metalloproteinases (MMPs)-9, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention when compared with standard therapy alone [14]
In vitro studies Effects of BBR and its derivatives on extracellular matrix metalloproteinase inducer (EMMPRIN) expression Since EMMPRIN functions as an upstream regulator of MMPs such as MMP-9 [22,23], we compared the effects of BBR and its derivatives on EMMPRIN expression by flow cytometric analysis and Western blotting
Summary
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. In the early course of the disease, monocytes adhere to dysfunctional vascular endothelium and migrate into the subendothelial layer of the intima where they differentiate into macrophages. These macrophages transform into foam cells when the subendothelial space is enriched with atherogenic lipoproteins [3]. Macrophage and foam cells express several matrix metalloproteinases (MMPs), such as MMP-9 and extracellular matrix metalloproteinase inducer (EMMPRIN) [5,6], which, in turn, contribute to vulnerability of atherosclerotic plaques [7,8]. Reducing atherosclerotic plaque size and preventing the rupture of vulnerable plaques are essential to preventing emergency medical conditions. In view of the important roles of MMP-9 and EMMPRIN in vulnerability of atherosclerotic plaques, MMP-9 and EMMPRIN are potential targets for therapeutic inventions to inhibit plaque rupture and acute medical conditions
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