Novel role of the nutraceutical bioactive compound berberine in lectin-like OxLDL receptor 1-mediated endothelial dysfunction in comparison to lovastatin

作者：Caliceti C^*; Rizzo P; Ferrari R; Fortini F; Aquila G; Leoncini E; Zambonin L; Rizzo B; Calabria D; Simoni P; Mirasoli M; Guardigli M; Hrelia S; Roda A; Cicero A F G

来源：Nutrition Metabolism and Cardiovascular Diseases, 2017, 27(6): 552-563.

DOI：10.1016/j.numecd.2017.04.002

• Endothelial dysfunction
• Berberine
• Lovastatin
• oxLDL receptor-1
• Reactive oxygen species
• Tumor necrosis factor alpha
• oxLDL

Background and aims: Oxidized LDL (oxLDL) or pro-inflammatory stimuli lead to increased oxidative stress linked to endothelial dysfunction and atherosclerosis. The oxLDL receptor-1 (LOX1) is elevated within atheromas and cholesterol-lowering statins inhibit LOX1 expression. Berberine (BBR), an alkaloid extracted from plants of gender Berberis, has lipidlowering and anti-inflammatory activity. However, its role in regulating LOX1-mediated signaling is still unknown. The aim of this study was to investigate the effect of BBR on oxLDLand TNFa-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs) and to compare it with that of lovastatin (LOVA).
Methods and results: Cytotoxicity was determined by lactate dehydrogenase assay. Antioxidant capacity was measured with chemiluminescent and fluorescent method and intracellular ROS levels through a fluorescent dye. Gene and protein expression levels were assayed by qRT-PCR and western blot, respectively.
HUVECs exposure to oxLDL (30 mu g/ml) or TNF alpha (10 ng/ml) for 24 h led to a significant increase in LOX1 expression, effect abrogated by BBR (5 mM) and LOVA (5 mM). BBR but not LOVA treatment abolished the TNF alpha-induced cytotoxicity and restored the activation of Akt signaling. In spite of a low direct antioxidant capacity, both compounds reduced intracellular ROS levels generated by treatment of TNF alpha but only BBR inhibited NOX2 expression, MAPK/Erk1/2 signaling and subsequent NF-kappa B target genes VCAM and ICAM expression, induced by TNF alpha.
Conclusions: These findings demonstrated for the first time that BBR could prevent the oxLDL and TNFa -induced LOX1 expression and oxidative stress, key events that lead to NOX, MAPK/Erk1/2 and NF-kappa B activation linked to endothelial dysfunction.
Chemical compounds studied in this article: Berberine (PubChem CID: 2353); Lovastatin (PubChem CID: 53232). (C) 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V.

• 出版日期2017-6