cyanidin-3-o-beta-glucopyranoside and Hypercholesterolemia

Controlling platelet granule secretion has been considered an effective strategy to dampen thrombosis and prevent atherosclerosis. Anthocyanins are natural plant pigments and possess a wide range of biological activities, including cardiovascular protective activity. In the present study we explored the effects and the potential mechanisms of anthocyanins on platelet granule secretion in hypercholesterolemia. In a randomised, double-blind clinical trial, 150 hypercholesterolaemic individuals were treated with purified anthocyanins (320 mg/day) or placebo for 24 weeks. Anthocyanins consumption significantly reduced plasma levels of β-thromboglobulin (β-TG), soluble P-selectin, and of Regulated on Activation Normal T cell Expressed and Secreted (RANTES) as compared with the placebo. A minor reduction in platelet factor 4 (PF4) and transforming growth factor β1 (TGF-β1) levels were also observed. In in vitro experiments, we observed that puriӿed anthocyanin mixture, as well as its two main anthocyanin components, delphinidin-3-glucoside (Dp-3-g) and cyanidin-3-glucoside (Cy-3g) directly inhibited platelet á-granule, dense granule, and lysosome secretion evaluated by P-selectin, RANTES, β-TG, PF4, TGF-β1, serotonin, ATP, and CD63 release. Further, anthocyanins inhibited platelet PI3K/Akt activation and consequently attenuated eNOS phosphorylation and cGMP production, thus interrupting MAPK activation. LY294002, a PI3K inhibitor, did not cause additional inhibitory efficacy, indicating that anthocyanin-induced effects may be involved in inhibition of the PI3K/Akt signalling pathway. These results provide evidence that by inhibiting platelet granule secretion, anthocyanins may be a potent cardioprotective agent.

Topics: Adenosine Triphosphate; Adult; Anthocyanins; Blood Platelets; Blood Proteins; Cardiotonic Agents; Cytoplasmic Granules; Double-Blind Method; Female; Glucosides; Humans; Hypercholesterolemia; Intercellular Signaling Peptides and Proteins; Lysosomes; Male; MAP Kinase Signaling System; Middle Aged; Phosphatidylinositol 3-Kinases; Phosphorylation; Phytotherapy; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Signal Transduction

The present study investigated the underlying mechanism associated with the hypocholesterolemic activity of blueberry anthocyanins by examining its effect on fecal sterol excretion and gene expression of major receptors, enzymes, and transporters involved in cholesterol metabolism.. Hamsters were divided into three groups and fed a 0.1 % cholesterol diet containing 0 % (CTL), 0.5 % (BL), and 1.0 % (BH) blueberry anthocyanins, respectively, for six weeks. Plasma total cholesterol (TC), triacylglycerols (TAG), and non-high-density lipoproteins cholesterol (non-HDL-C) were measured using the enzymatic kits, and the gene expression of transporters, enzymes, and receptors involved in cholesterol absorption and metabolism was quantified using the quantitative PCR. GC analysis was used to quantify hepatic cholesterol and fecal acidic and neutral sterols.. Dietary supplementation of 0.5 and 1.0 % blueberry anthocyanins for 6 weeks decreased plasma TC concentration by 6-12 % in a dose-dependent manner. This was accompanied by increasing the excretion of fecal neutral and acidic sterols by 22-29 % and 41-74 %, respectively. Real-time PCR analyses demonstrated that incorporation of blueberry anthocyanins into diet down-regulated the genes of NPC1L1, ACAT-2, MTP, and ABCG 8. In addition, blueberry anthocyanins were also able to down-regulate the gene expression of hepatic HMG-CoA reductase.. The cholesterol-lowering activity of blueberry anthocyanins was most likely mediated by enhancing the excretion of sterols accompanied with down-regulation on gene expression of intestinal NPC1L1, ACAT-2, MTP, and ABCG 8.

Topics: Animals; Anthocyanins; Anticholesteremic Agents; ATP-Binding Cassette Transporters; Blueberry Plants; Carrier Proteins; Cricetinae; Feces; Fruit; Glucosides; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Intestine, Small; Liver; Male; Mesocricetus; Phytotherapy; Plant Extracts; Sterol O-Acyltransferase; Sterol O-Acyltransferase 2; Sterols

Four polyphenols: ferulic acid and p-coumaric acid (hydroxycinnamic acids), quercetin (flavonol) and cyanidin 3-glucoside (anthocyanin) were selected, and their antioxidant properties and their influence on cholesterol concentration in hypercholesterolemic and normal erythrocytes were investigated.. To determine the effect of phenolic compounds, we prospectively studied cholesterol concentration, lipid peroxidation and membranes fluidity. Whole-blood and isolated erythrocytes (2% hematocrit) were incubated for 24 h with selected compounds at concentration 1, 10 and 100 μmol/L. All investigated compounds decreased lipid peroxidation in whole blood. Cyanidin 3-glucoside and quercetin showed higher antioxidant properties than hydroxycinnamic acids (ferulic acid and p-coumaric acid).. Incubation of whole blood of hypercholesterolemic patients with quercetin and cyanidin 3-glucoside resulted in statistically significant reduction of cholesterol concentration in erythrocytes down to 75% (at 10 μmol/L of polyphenols) and 69% (at 100 μmol/L of polyphenols) of initial values. The effect of both compounds on isolated erythrocytes was even more pronounced, reduction down to 70% (at 10 μmol/L of polyphenols) and 58% (at 100 μmol/L of polyphenols) of initial values. After incubation of isolated erythrocytes of hypercholesterolemic patients with quercetin and cyanidin 3-glucoside, increase of membrane fluidity was noticed. After incubation of isolated erythrocytes of healthy donors with investigated compounds, no changes in membrane fluidity were observed.. Our results indicate that flavonols and anthocyanins have higher antioxidant properties and higher influence on cholesterol concentration in erythrocytes membranes than simple hydroxycinnamic acids.

Topics: Anthocyanins; Antioxidants; Cholesterol; Coumaric Acids; Dietary Supplements; Erythrocyte Membrane; Erythrocytes; Glucosides; Humans; Hypercholesterolemia; Hypolipidemic Agents; Lipid Peroxidation; Male; Membrane Fluidity; Middle Aged; Osmolar Concentration; Propionates; Quercetin; Thiobarbituric Acid Reactive Substances

Although previous studies have shown that consumption of anthocyanin extract from plant foods reduces hypercholesterolemia and the severity of atherosclerosis in different animal models, the mechanisms of these actions remained unclear. This study investigated whether pure anthocyanin inhibit atherosclerosis development and reduce hypercholesterolemia in the apolipoprotein E (ApoE)-deficient mice through enhancement of fecal bile acid excretion, a critical pathway for eliminating circulation cholesterol from the body.. Five-week-old male ApoE-deficient mice were fed the AIN-93G diet supplemented with or without cyanidin-3-O-β-glucoside (0.06% w/w) for 12 weeks. Results showed that cyanidin-3-O-β-glucoside consumption inhibited the formation of aortic sinus plaque and reduced hypercholesterolemia, along with promoted fecal bile acid excretion and upregulated hepatic cholesterol 7a-hydroxylase expression (CYP7A1). In mouse primary hepatocytes, cyanidin-3-O-β-glucoside treatment increased bile acid synthesis and CYP7A1 expression in a liver X receptor alpha (LXRα)-)-dependent manner. Scintillation proximity and time-resolved fluorescence resonance energy transfer assays revealed that cyanidin-3-O-β-glucoside functions as an agonist of LXRα.. Our results indicate that the hypocholesterolemic activity of cyanidin-3-O-β-glucoside was, at least in part, mediated by activating the potential LXRα-CYP7A1-bile acid excretion pathway, thus contributing to the antiatherogenic effect of cyanidin-3-O-β-glucoside. Importantly, cyanidin-3-O-β-glucoside could activate LXRα in an agonist-dependent manner.

Topics: Animals; Anthocyanins; Apolipoproteins E; Atherosclerosis; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase; Gene Knockdown Techniques; Glucosides; Hepatocytes; Hypercholesterolemia; Liver; Liver X Receptors; Male; Mice; Orphan Nuclear Receptors; Up-Regulation

In this study, we investigated the protective effects of the anthocyanin cyanidin-3-O-β-glucoside (C3G) on hypercholesterolemia-induced endothelial dysfunction in apoE-deficient (apoE(-/-)) mice. In the prevention study, twenty 8-wk-old male apoE(-/-) mice (n = 10/group) were fed a high-fat, cholesterol-rich diet (HCD) or the HCD supplemented with C3G (2 g/kg diet) for 8 wk. The endothelium-dependent relaxation response to acetylcholine in the aortas of the C3G-fed mice was greater compared with those fed the HCD (P < 0.05). The atherosclerotic plaque area in the aortic sinus of mice fed the C3G diet was lowered by 54% compared with those fed the HCD (P < 0.01). Mice fed C3G had greater expression of the ATP-binding cassette transporter G1 (ABCG1) and lower cholesterol, mainly 7-ketocholesterol (7-KC), concentrations than those fed the HCD. Superoxide production and lipid hydroperoxides in aorta were lower in mice fed C3G compared with those fed the HCD. The phosphorylation levels at Ser1177 of endothelial NO synthase (eNOS) and the production of cyclic GMP (cGMP) in aorta were greater in C3G-fed mice than in HCD-fed mice. In the therapy study, apoE(-/-) mice were fed the HCD for 8 wk and then continued to receive the HCD or were switched to the HCD supplemented with C3G (2 g/kg diet) for another 8 wk. The established endothelial dysfunction and atherosclerosis were reversed, accompanied by greater ABCG1 expression in aorta, lower cholesterol and 7-KC concentrations, and greater generation of cGMP in mice fed C3G compared with those fed the HCD. Taken together, our results show that the anthocyanin C3G prevents or reverses hypercholesterolemia-induced endothelial dysfunction by inhibiting cholesterol and 7-oxysterol accumulation in the aorta and the subsequent decrease in superoxide production, thereby preserving eNOS activity and NO bioavailability.

Topics: Animals; Anthocyanins; Aorta; Apolipoproteins E; Atherosclerosis; Dietary Fats; Dietary Supplements; Endothelium, Vascular; Glucosides; Hypercholesterolemia; Hypolipidemic Agents; Male; Mice; Mice, Knockout; Nitric Oxide; Oxidative Stress