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      Effect of a rosmarinic acid supplemented hemodialysis fluid on inflammation of human vascular endothelial cells

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          Abstract

          Chronic systemic inflammation and repetitive damage of vascular endothelia by incompatible dialysis system are probable causes of cardiovascular disease in patients on dialysis. The present study aimed to assess in vitro biocompatibility and anti-inflammatory effect of hemodialysis fluid supplemented with rosmarinic acid (RA) using human umbilical vein endothelial cells (HUVEC). HUVECs (5×10 6 cells/mL) were pre-exposed to 1 μg/mL of lipopolysaccharides (LPS) and incubated with RA-supplemented hemodialysis fluid (HDF). Cytotoxicity was assessed qualitatively by morphologic assessment and quantitatively by MTT assay. Expressions of proinflammatory mediators were assessed using quantitative real-time PCR and production of NO was quantified. Phosphorylation of AKT and nuclear localization of nuclear factor kappa B (NF-κB) were examined using western blotting. Exposure of HUVECs to RA-supplemented HDF had no influence on morphology and viability. Inhibition of proinflammatory mediator production in HUVECs by RA supplementation to HDF was significant in a dose-dependent manner. Exposure to RA-supplemented HDF resulted in a decrease in nitric oxide synthase expression and reduction of NO production in LPS-stimulated HUVECs. RA supplementation of HDF suppressed Akt activation in LPS-stimulated HUVECs. In addition, the level of cellular IκB was increased in parallel to a reduced nuclear translocation of NF-κB in LPS-induced endothelial cells. Our results suggest that RA-supplemented HDF is biocompatible and significantly suppressed inflammation induced in endothelial cells. In this respect, the use of HDF supplemented with RA could alleviate inflammation and improve long-term treatment of patients with renal failure on dialysis. Further clinical studies are required to confirm the effects.

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          Most cited references 41

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          Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease.

          Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation, were studied during a mean follow-up period of 4.5 years. Patients experiencing cardiovascular events (n=91) had lower vasodilator responses to acetylcholine (P<0.001) and sodium nitroprusside (P<0.05), but greater benefit from vitamin C (P<0.01). The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation (P=0.001), the effect of vitamin C (P=0.001), and age (P=0.016) remained independent predictors of cardiovascular events. Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease. These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity.
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            Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway.

            Elevated levels of interleukin-6 (IL-6) have been identified in a variety of systemic inflammatory states that are associated with endothelial barrier dysfunction, but the specific effect of IL-6 on endothelial permeability and the mechanism of action have not been fully examined. The current study evaluated the effect of IL-6 on endothelial permeability and on the distribution of the tight junctional protein ZO-1 and cytoskeletal actin. We also assessed the role of protein kinase C (PKC) in this process. Confluent monolayers of human umbilical vein endothelial cells (n = 6) were exposed to IL-6 (50-500 ng/ml) in the presence or absence of the PKC inhibitor Gö6976 (0.1 microM). Transendothelial electrical resistance (TEER) was measured at the onset of exposure and at 6-h intervals and compared with that of control cells using ANOVA with a Bonferroni multiple comparison test. Additional monolayers were exposed to IL-6, stained for ZO-1 and F-actin, and evaluated via fluorescence microscopy. Interleukin-6 increased endothelial permeability as measured by TEER in a dose- and time-dependent manner. In the presence of PKC inhibitor, the IL-6-mediated increase in permeability was attenuated (18-h TEER 73% of control with IL-6 exposure vs 95% of control with IL-6 + Gö6976 inhibitor, P < 0.01). Microscopy revealed that permeability changes were accompanied by a redistribution of the tight junctional protein ZO-1 and cytoskeletal actin, increased cell contraction, and disorganization of the intercellular borders. Conclusions. The inflammatory cytokine IL-6 is an important mediator of increased endothelial permeability via alterations in the ultrastructural distribution of tight junctions and morphologic changes in cell shape. PKC is a critical intracellular messenger in these IL-6-mediated changes. A better understanding of this mechanism should allow the determination of rational treatment strategies for endothelial barrier dysfunction which occurs in inflammatory states. (c) 2002 Elsevier Science (USA).
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              Rosmarinic acid, a new snake venom phospholipase A2 inhibitor from Cordia verbenacea (Boraginaceae): antiserum action potentiation and molecular interaction.

              Many plants are used in traditional medicine as active agents against various effects induced by snakebite. The methanolic extract from Cordia verbenacea (Cv) significantly inhibited paw edema induced by Bothrops jararacussu snake venom and by its main basic phospholipase A2 homologs, namely bothropstoxins I and II (BthTXs). The active component was isolated by chromatography on Sephadex LH-20 and by RP-HPLC on a C18 column and identified as rosmarinic acid (Cv-RA). Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid [2-O-cafeoil-3-(3,4-di-hydroxy-phenyl)-R-lactic acid]. This is the first report of RA in the species C. verbenacea ('baleeira', 'whaler') and of its anti-inflammatory and antimyotoxic properties against snake venoms and isolated toxins. RA inhibited the edema and myotoxic activity induced by the basic PLA2s BthTX-I and BthTX-II. It was, however, less efficient to inhibit the PLA2 activity of BthTX-II and, still less, the PLA2 and edema-inducing activities of the acidic isoform BthA-I-PLA2 from the same venom, showing therefore a higher inhibitory activity upon basic PLA2s. RA also inhibited most of the myotoxic and partially the edema-inducing effects of both basic PLA2s, thus reinforcing the idea of dissociation between the catalytic and pharmacological domains. The pure compound potentiated the ability of the commercial equine polyvalent antivenom in neutralizing lethal and myotoxic effects of the crude venom and of isolated PLA2s in experimental models. CD data presented here suggest that, after binding, no significant conformation changes occur either in the Cv-RA or in the target PLA2. A possible model for the interaction of rosmarinic acid with Lys49-PLA2 BthTX-I is proposed.
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                Author and article information

                Journal
                Braz J Med Biol Res
                Braz. J. Med. Biol. Res
                bjmbr
                Brazilian Journal of Medical and Biological Research
                Associação Brasileira de Divulgação Científica
                0100-879X
                1414-431X
                19 October 2017
                2017
                : 50
                : 12
                Affiliations
                [1 ]Department of Biomedical Engineering, Chung Yuan Christian University, Chungli, Taiwan
                [2 ]Division of Nephrology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
                [3 ]Department of Rehabilitation, TaoYuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
                Author notes
                Correspondence: C-S. Weng: < jasonheartyman@ 123456yahoo.com.tw >
                Article
                00606
                10.1590/1414-431X20176145
                5649864
                29069222

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 35, Pages: 1
                Categories
                Research Articles

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