Abstract
AimsBerberine, a botanical alkaloid purified from Coptidis rhizoma, is reported to activate the AMP-activated protein kinase (AMPK). Whether AMPK is required for the protective effects of berberine in cardiovascular diseases remains unknown. This study was designed to determine whether AMPK is required for berberine-induced reduction of oxidative stress and atherosclerosis in vivo.MethodsApoE (ApoE-/-) mice and ApoE-/-/AMPK alpha 2-/- mice that were fed Western diets were treated with berberine for 8 weeks. Atherosclerotic aortic lesions, expression of uncoupling protein 2 (UCP2), and markers of oxidative stress were evaluated in isolated aortas.ResultsIn ApoE-/- mice, chronic administration of berberine significantly reduced aortic lesions, markedly reduced oxidative stress and expression of adhesion molecules in aorta, and significantly increased UCP2 levels. In contrast, in ApoE-/-/AMPK alpha 2-/- mice, berberine had little effect on those endpoints. In cultured human umbilical vein endothelial cells (HUVECs), berberine significantly increased UCP2 mRNA and protein expression in an AMPK-dependent manner. Transfection of HUVECs with nuclear respiratory factor 1 (NRF1)-specific siRNA attenuated berberine-induced expression of UCP2, whereas transfection with control siRNA did not. Finally, berberine promoted mitochondrial biogenesis that contributed to up-regulation of UCP2 expression.ConclusionWe conclude that berberine reduces oxidative stress and vascular inflammation, and suppresses atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression.
Highlights
Berberine is an isoquinolone alkaloid found in plants such as Phellodendron chinense and Coptis chinensis
Materials Antibodies against phospho-AMPK, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, 4-hydroxy-trans-2-nonenal (4-HNE), 3-nitrotryosine (3-NT) and b-actin were obtained from Cell Signaling Biotechnology (Danvers, MA)
We first evaluated the effects of berberine on the severity of aortic atherosclerosis in ApoE-/- and ApoE-/-/AMPK alpha 2-/- mice maintained on this diet
Summary
Berberine is an isoquinolone alkaloid found in plants such as Phellodendron chinense and Coptis chinensis. In traditional Chinese medicine, berberine from Coptidis rhizoma is used as a constituent of the herbal medicine Huanglian. In this form it is reported to exert anti-fungal, anti-bacterial/viral, and anti-oncogenic effects, as well as a beneficial effect on diabetes [1,2,3,4,5], and anti-atherogenic properties [6,7,8]. Several mechanisms are reported to be associated with the beneficial properties of berberine including improvement of endothelial function and dyslipidemia, inhibition of low-density lipoprotein oxidation, and decreased blood pressure. The molecular targets through which berberine exerts its beneficial effects are undefined
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