Supplementation with cyanidin-3-O-β-glucoside protects against hypercholesterolemia-mediated endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E-deficient mice.
ABSTRACT 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.
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ABSTRACT: Anthocyanins (AC) are water-soluble natural pigments found in various parts of higher plants. Despite their limited oral bioavailability and very low post-absorption plasma concentrations, the dietary consumption of these pigments has been proposed to be associated with a significant protection against several human pathological conditions, including cardiovascular diseases. Many studies highlighted that some health benefits of AC localize in particular at endothelium level, contributing to vascular homeostasis and also to the control of angiogenesis, inflammation, and platelet aggregation. This review reports and comments on the large existing literature addressing the molecular mechanisms that, beyond the antioxidant properties, may have a significant role in the effects of AC and AC-rich foods on vessel endothelium. Among these, AC have been reported to prevent peroxynitrite-mediated endothelial dysfunction in endothelial cells (ECs), thanks to their capability to modulate the expression and activity of several enzymes involved in NO metabolism. Furthermore, evidence indicates that AC can prevent the expression of adhesion molecules and the adhesion of monocytes to ECs challenged by pro-inflammatory agents. Overall, the activity of AC could be associated with the ability to elicit cell adaptive responses involving the transcription factor Nrf2 by affecting the "nucleophilic tone" of the organism. This review confirms the importance of specific nutritional molecules for human health and suggests new avenues for nutrition-based interventions to reduce the risk of cardiovascular disease in the population.Genes & Nutrition 07/2014; 9(4):404. · 3.33 Impact Factor
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ABSTRACT: Oxysterol is associated with the induction of endothelial oxidative stress and impaired endothelial function. Mitochondria play a central role in oxidative energy metabolism and the maintenance of proper redox status. The purpose of this study was to determine the effects and mechanisms of 7-ketocholesterol (7-KC) on isocitrate dehydrogenase 2 (IDH2) and its impact on endothelial function in both human aortic endothelial cells (HAECs) and C57BL/6J mice. HAECs treated with 7-KC showed significant reductions of IDH2 mRNA and protein levels and enzyme activity, leading to decreased NADPH concentration and an increased ratio of reduced-to-oxidized glutathione in the mitochondria. 7-KC induced the expression of a specific microRNA, miR-144, which in turn targets and downregulates IDH2. In silico analysis predicted that miR-144 could bind to the 3' untranslated region of IDH2 mRNA. Overexpression of miR-144 decreased the expression of IDH2 and the levels of NADPH. A complementary finding is that a miR-144 inhibitor increased the mRNA and protein expression levels of IDH2. Furthermore, miR-144 level was elevated in HAECs in response to 7-KC. Anti-Ago1/2 immunoprecipitation coupled with a real-time polymerase chain reaction assay revealed that 7-KC increased the functional targeting of miR-144/IDH2 mRNA in HAECs. Infusion of 7-KC in vivo decreased vascular IDH2 expression and impaired vascular reactivity via miR-144. 7-KC controls miR-144 expression, which in turn decreases IDH2 expression and attenuates NO bioavailability to impair endothelial homeostasis. The newly identified 7-KC-miR-144-IDH2 pathway may contribute to atherosclerosis progression and provides new insight into 7-KC function and microRNA biology in cardiovascular disease.Free Radical Biology & Medicine 03/2014; · 5.27 Impact Factor
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ABSTRACT: Diets supplemented with fish oil (FO), which is rich in n-3 PUFA, have been shown to modify several key risk factors for CVD. The purpose of the present study was to determine the effect of FO supplementation on mitochondrial dynamic protein expression in the endothelium and on endothelial cell function. Male apoE-deficient (apoE- / -) mice (8 weeks old, n 12 per group) were fed a high-fat diet containing 45 % fat (HFD group) or a HFD with partial replacement of lard with 10 % (w/w) FO (FO group) (total EPA and DHA content 64·1 g/kg) for 8 weeks. ApoE- / - mice in the FO group had a greater endothelium-dependent vasorelaxation response to acetylcholine (Ach) than those in the HFD group. The atherosclerotic lesion volume in the aortic sinus of mice in the FO group was 54 % lower than that in the HFD group (P< 0·01). In addition, the aortas isolated from mice in the FO group had higher expression levels of Mfn2 and Opa1 but lower expression levels of Fis1 than those from the HFD group. Compared with mice fed the HFD, those fed the FO diet showed significantly lower levels of mitochondrial oxidative stress, cytochrome c release and caspase-3 activity (each P< 0·05). Furthermore, FO-fed mice displayed increased NO release and availability and enhanced endothelial NO synthase activity compared with HFD-fed mice. Taken together, these results reveal a novel mechanism by which FO protects against endothelial cell dysfunction, which may result in improved mitochondrial dynamics.The British journal of nutrition 04/2014; · 3.45 Impact Factor