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Background: Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood., Objectives: We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined., Methods: Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8-9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum lipid profile and proinflammatory cytokine TNF-α concentrations, gut microbiota, and liver TNF-α and fatty acid synthase (Fasn) mRNA concentrations were assessed., Results: F&V supplementation did not affect weight gain. Mice fed the Ath + FV diet had a smaller aortic atherosclerotic lesion area (71.7% less) and hepatic steatosis area (80.7% less) than those fed the Ath diet (both P < 0.001) independent of impact on weight, whereas no difference was found between Ath + FV and CON groups in these 2 pathologic markers. Furthermore, F&V supplementation prevented Ath diet-induced dyslipidemia (high concentrations of serum TG and VLDL cholesterol and lower concentrations of HDL cholesterol), reduced serum TNF-α concentration (by 21.5%), suppressed mRNA expression of liver TNF-α and Fasn, and ameliorated Ath-induced gut microbiota dysbiosis., Conclusions: Our results indicate that consuming a large quantity and variety of F&Vs causally attenuates diet-induced atherosclerosis and hepatic steatosis in mice. These effects of F&Vs are associated with, and may be mediated through, improved atherogenic dyslipidemia, alleviated gut dysbiosis, and suppressed inflammation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Platelets play an important role in hemostasis, thrombosis, and atherosclerosis. Glycoprotein VI (GPVI) is a major platelet receptor that interacts with exposed collagen on injured vessel walls. Our previous studies have shown that anthocyanins (a type of natural plant pigment) attenuate platelet function; however, whether anthocyanins affect collagen-induced GPVI signaling remains unknown. Objective: The objective of this study was to explore the effects of cyanidin-3-glucoside (Cy-3-g, one of the major bioactive compounds in anthocyanins) on platelet activation and thrombosis and the GPVI signaling pathway. Methods: Platelets from healthy men and women were isolated and incubated with different concentrations (0, 0.5, 5, and 50 μM) of Cy-3-g. The expression of activated integrin αIIbβ3, P-selectin, CD63, and CD40L, fibrinogen binding to platelets, and platelet aggregation were evaluated in vitro. Platelet adhesion and aggregation in whole blood under flow conditions were assessed in collagen-coated perfusion chambers. Thrombosis and hemostasis were assessed in 3-4-wk-old male C57BL/6J mice through FeCl 3 -induced intravital microscopy and tail bleeding time. The effect of Cy-3-g on collagen-induced human platelet GPVI signaling was explored with Western blot. Results: Cy-3-g attenuated platelet function in a dose-dependent manner. The 0.5-μM dose of Cy-3-g inhibited ( P < 0.05) human platelet adhesion and aggregation to collagen at both venous (-54.02%) and arterial (-22.90%) shear stresses. The 5-μM dose inhibited ( P < 0.05) collagen-induced human platelet activation (PAC-1: -48.21%, P-selectin: -50.63%), secretion (CD63: -73.89%, CD40L: -43.70%), fibrinogen binding (-56.79%), and aggregation (-17.81%). The 5-μM dose attenuated ( P < 0.01) thrombus growth (-66.67%) without prolonging bleeding time in mice. The 50-μM dose downregulated ( P < 0.05) collagen-induced GPVI signaling in human platelets and significantly decreased phosphorylation of Syk-linker for activation of T cells (LAT)-SLP76 (Syk: -39.08%, LAT: -32.25%, SLP76: -40.00%) and the expression of Lyn (-31.89%), Fyn (-36.27%), and phospholipase C-γ2 (-39.08%). Conclusions: Cy-3-g inhibits human platelet activation, aggregation, secretion, and thrombus formation, and downregulates the collagen-GPVI signaling pathway. Supplementation of Cy-3-g may have protective effects against atherothrombosis., Competing Interests: Author disclosures: Y Yao, YC, RA, TM, PC, GZ, DL, WL, HN, and Y Yang, no conflicts of interest., (© 2017 American Society for Nutrition.)

Chronic inflammation and proatherogenic lipids are important risk factors of cardiovascular disease (CVD). Specific dietary constituents such as polyphenols and fish oils may improve cardiovascular risk factors and may have a beneficial effect on disease outcomes. We hypothesized that the intake of an antiinflammatory dietary mixture (AIDM) containing resveratrol, lycopene, catechin, vitamins E and C, and fish oil would reduce inflammatory risk factors, proatherogenic lipids, and endpoint atherosclerosis. AIDM was evaluated in an inflammation model, male human C-reactive protein (CRP) transgenic mice, and an atherosclerosis model, female ApoE*3Leiden transgenic mice. Two groups of male human-CRP transgenic mice were fed AIDM [0.567% (wt:wt) powder and 0.933% (wt:wt oil)] or placebo for 6 wk. The effects of AIDM on basal and IL-1β-stimulated CRP expression were investigated. AIDM reduced cytokine-induced human CRP and fibrinogen expression in human-CRP transgenic mice. In the atherosclerosis study, 2 groups of female ApoE*3Leiden transgenic mice were fed an atherogenic diet supplemented with AIDM [0.567% (wt:wt) powder and 0.933% (wt:wt oil)] or placebo for 16 wk. AIDM strongly reduced plasma cholesterol, TG, and serum amyloid A concentrations compared with placebo. Importantly, long-term treatment of ApoE*3Leiden mice with AIDM markedly reduced the development of atherosclerosis by 96% compared with placebo. The effect on atherosclerosis was paralleled by a reduced expression of the vascular inflammation markers and adhesion molecules inter-cellular adhesion molecule-1 and E-selectin. Dietary supplementation of AIDM improves lipid and inflammatory risk factors of CVD and strongly reduces atherosclerotic lesion development in female transgenic mice.

Protective effects of blueberries (BB) against atherosclerosis and potential underlying mechanisms in reducing oxidative stress were examined in apoE-deficient (apoE(-/-)) mice. ApoE(-/-) mice were fed an AIN-93G diet (CD) or CD formulated to contain 1% freeze-dried whole BB for 20 wk. The mean lesion area for apoE(-/-) mice fed BB was reduced by 39% (P < 0.001) in the aorta sinus and 58% (P < 0.001) in the descending aorta compared with CD-fed mice. These atheroprotective effects were independent of the serum lipid profile or total antioxidant capacity (as measured by oxygen radical absorbance capacity). The concentration of a biomarker of lipid peroxidation, F(2)-isoprostane, was lower in liver of BB-fed mice (P < 0.05). Genes analyzed by RT-PCR array showed that 4 major antioxidant enzymes in aorta [superoxide dismutase (SOD) 1, SOD2, glutathione reductase (GSR), and thioredoxin reductase 1] were upregulated in BB-fed mice. Enzyme activities of SOD and GSR were greater (P < 0.05) in liver and/or serum of BB-fed mice than those of CD-fed mice. In addition, serum paraoxonase 1 activity in serum of BB-fed mice was also greater than that of CD-fed mice (P < 0.05) at the end of the study. These results suggest a protective effectiveness of BB against atherosclerosis in this apoE(-/-) mouse model. The potential mechanisms may involve reduction in oxidative stress by both inhibition of lipid peroxidation and enhancement of antioxidant defense.

Recent studies of the relation between serum triacylglycerol concentration and the risk for coronary artery disease suggest that inefficient clearance of postprandial triacylglycerols promotes atherogenesis. We recently demonstrated that dietary diacylglycerol (DAG), rich in the 1,3-species, suppresses the postprandial increase in serum triacylglycerol levels compared with dietary triacylglycerol (TAG). Here, we investigated the effects of dietary DAG on atherosclerosis in rabbits with cholesterol-induced atherosclerosis. New Zealand White rabbits (n = 20) were fed a diet containing 3% lard and 1.3% cholesterol for 50 d to induce atherosclerotic lesions. Thereafter, the rabbits were assigned to 2 groups and fed 90 g/d nonpurified diet and orally administered 5 g DAG or TAG for an additional 34 d. Reference rabbits (n = 5) were fed only the nonpurified diet throughout the 84-d study. The area of atherosclerotic lesions and aortic lipid concentrations were significantly lower in DAG-fed rabbits compared with TAG-fed rabbits. The VLDL receptor and macrophage antigen-1 mRNA expression levels were significantly lower in DAG-fed rabbits than in TAG-fed rabbits. In the liver of DAG-fed rabbits, the triacylglycerol concentration was lower and the carnitine palmitoyltransferase activity higher than in TAG-fed rabbits. Stimulation of hepatic lipid catabolism might be related to the reduced lipid accumulation in the liver and aorta by reducing the release of triacylglycerol into the circulation. Thus, long-term consumption of DAG, which reduces postprandial lipemia, might be useful for the regression of atherosclerosis by stimulating hepatic lipid catabolism and thereby modulating monocyte/macrophage migration and aortic lipid accumulation.

To gain insight into the regulation of hepatic sterol-responsive genes that are thought to mediate the hypocholesterolemic effects of guar gum (GG) consumption, the mRNA and protein expression of sterol regulatory element binding protein 2 (SREBP2), LDL receptor (LDLr), and scavenger receptor class B, type 1 (SR-B1) were examined in pigs consuming an atherogenic control diet or the control diet supplemented with 10% GG. Compared with the control group, GG consumption reduced (P < 0.05) plasma total cholesterol and LDL cholesterol concentrations by 27 and 37%, respectively. Furthermore, hepatic free cholesterol concentration was lower (P < 0.05) in the GG-fed pigs in comparison with the control group. GG consumption increased hepatic LDLr mRNA (1.5-fold of the control, P = 0.09) and protein (2-fold of the control, P < 0.05) expression in comparison with the control group. However, GG consumption reduced hepatic SR-B1 mRNA to 36% of the control (P < 0.05) expression but did not affect (P = 0.19) SR-B1 protein abundance in comparison with the control group. Although SREBP2 mRNA expression was similar (P = 0.89) in the 2 groups, GG consumption increased (P < 0.05) the expression of the cytoplasmic precursor (3-fold of the control) and nuclear active forms (1.5-fold of the control) of SREBP2. We conclude that the hypocholesterolemic effects of GG consumption are related to a reduction in hepatic free cholesterol concentration and associated increases in nuclear active SREBP2 expression and hepatic LDLr abundance.

Dietary phytosterols significantly reduce atherosclerosis in apo E-deficient mice. Because atherosclerosis is a chronic inflammatory disease, we investigated whether the antiatherogenic effects of phytosterols are associated with reductions in proinflammatory cytokine production as well as the effect of this diet on global immunocompetence. Apolipoprotein (apo) E-deficient mice were fed a cholesterol-supplemented diet in the presence or absence of 2% dietary phytosterols for 14 wk and then immunized with ovalbumin. The relations between plasma lipid concentrations, atherosclerotic lesions, and cytokine production and proinflammatory stimuli or foreign antigens were characterized. Phytosterol-enriched diets were strongly associated with reduced plasma cholesterol concentrations and atherosclerosis in conjunction with higher anti-inflammatory [interleukin (IL)-10] and lower proinflammatory cytokine [IL-6, tumor necrosis factor (TNF)-alpha] production. In contrast, development of cytokine and chemokine responses to ovalbumin was as strong as or even improved in the phytosterol-treated mice relative to controls. The antiatherogenic effects of dietary phytosterols in apo E-knockout mice were associated with beneficial alterations in both lipoprotein metabolism and inflammatory pathways. Decreased capacity to mount proinflammatory cytokine and chemokine responses to inflammatory stimuli did not interfere with the global immunocompetence of such mice. Thus, the desirable suppression of proinflammatory cytokine production that was associated with inhibition of atherogenesis did not impair the capacity to mount responses to foreign antigens.