title: β-carotene reverses the IL-1β-mediated reduction in paraoxonase-1 expression via induction of the CaMKKII pathway in human endothelial cells.
abstract: Interleukin-1 beta (IL-1β) induces endothelial dysfunction and reduces nitric oxide (NO) production. IL-1β also enhances adhesion molecule expression and induces arteriosclerosis. Conversely, high-density lipoprotein (HDL) induces endothelial NO synthase (eNOS), paraoxonase-1 (PON-1) activity, and maintains vascular health. Diet-derived β-carotene prevents arteriosclerosis, but its mode of action is not understood. The purpose of this study was to examine the HDL-like mechanisms of β-carotene in endothelial cells. We added IL-1β and/or β-carotene to cultured human endothelial cells and examined its effects on the regulation of HDL signal transduction pathways using RT-PCR, real-time PCR, Western blot (WB), and endothelial-U937 adhesion analysis. IL-1β decreased the expression of Ca2+/calmodulin-dependent kinase II (CaMKII), eNOS, PON-1, phosphatidylinositol 3-kinase (PI3K), PSD-95/Dlg/ZO-1 (PZK1), and liver kinase B1 (LKB1). Conversely, it increased the expression of intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein 1 (MCP-1). In contrast, β-carotene increased the expression of CaMKKII, PI3K, PZK1, LKB1, eNOS, PON-1, and reduced the expression of ICAM-1 and MCP-1. β-carotene also induced phospho-AMP-activated protein kinase (p-AMPK), phospho-eNOS and PON-1 proteins. Importantly, β-carotene upregulated the IL-1β-mediated decrease of CaMKKII, PZK1, LKB1, eNOS and PON-1. β-carotene inhibited IL-1β-mediated cell adhesion of U937 to endothelial cells. The effect of β-carotene was reversed by a CaMKK inhibitor, STO-609. These findings indicate that β-carotene regulates the expression of PON-1, eNOS and adhesion molecules via CaMKK pathway activation. β-carotene may contribute to the functional maintenance of vascular endothelial cells in a manner similar to HDL, protecting them against stimuli such as IL-1β.
authors: Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University, Japan. kyamagat@brs.nihon-u.ac.jp
authors: Kazuo
authors: K
authors: Yamagata
authors: Noriko
authors: N
authors: Tanaka
authors: Hiroshi
authors: H
authors: Matsufuji
authors: Makoto
authors: M
authors: Chino
mesh_terms: D043303:Aryldialkylphosphatase / Q000096:biosynthesis*; D050197:Atherosclerosis / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D020298:U937 Cells; D019207:beta Carotene / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D053583:Interleukin-1beta; D019207:beta Carotene; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C517698:CAMKK2 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D043303:Aryldialkylphosphatase