Aortic Fatty Streak Research Articles

Loxin Reduced the Inflammatory Response in the Liver and the Aortic Fatty Streak Formation in Mice Fed with a High-Fat Diet.

Oxidized low-density lipoprotein (ox-LDL) is the most harmful form of cholesterol associated with vascular atherosclerosis and hepatic injury, mainly due to inflammatory cell infiltration and subsequent severe tissue injury. Lox-1 is the central ox-LDL receptor expressed in endothelial and immune cells, its activation regulating inflammatory cytokines and chemotactic factor secretion. Recently, a Lox-1 truncated protein isoform lacking the ox-LDL binding domain named LOXIN has been described. We have previously shown that LOXIN overexpression blocked Lox-1-mediated ox-LDL internalization in human endothelial progenitor cells in vitro. However, the functional role of LOXIN in targeting inflammation or tissue injury in vivo remains unknown. In this study, we investigate whether LOXIN modulated the expression of Lox-1 and reduced the inflammatory response in a high-fat-diet mice model. Results indicate that human LOXIN blocks Lox-1 mediated uptake of ox-LDL in H4-II-E-C3 cells. Furthermore, in vivo experiments showed that overexpression of LOXIN reduced both fatty streak lesions in the aorta and inflammation and fibrosis in the liver. These findings were associated with the down-regulation of Lox-1 in endothelial cells. Then, LOXIN prevents hepatic and aortic tissue damage in vivo associated with reduced Lox-1 expression in endothelial cells. We encourage future research to understand better the underlying molecular mechanisms and potential therapeutic use of LOXIN.

The effects of olive oil and cholesterol enriched diets on aortic fatty streak development and lipid peroxidation in rabbits.

High plasma cholesterol levels, mainly low-density lipoprotein-cholesterol (LDL) is a widely recognized major risk factor for coronary heart disease (CHD). According to epidemiologic studies' findings, people from the Mediterranean countries have lower CHD rates than other countries; in these countries the usual diet is high in olive oil. The present study compares the effects of a cholesterol-enriched diet with or without adding olive oil on serum lipoproteins, lipid peroxidation, and atherosclerosis development. Twenty Dutch male rabbits were categorized into four groups (one group as control, and others as experimental). They received one of control (CON), olive oil-rich (OIL), cholesterol-rich (CHOL), and cholesterol + olive oil (COIL) diet for 12 weeks. Fasting blood samples from the heart were collected at the beginning and the end of the experimental period. Means of serum lipids were not significantly different at the beginning of the experimental period. After the intervention, significant differences were shown in total cholesterol (TC) (CON: 27.75 ± 4.83, OIL: 19.75 ± 2.62, CHOL: 1757.20 ± 149.62, COIL: 2906.40 ± 421.01; P < 0.001), high-density lipoprotein-cholesterol (HDL-C) (CON: 16 ± 1.47, OIL: 10.25 ± 1.70, CHOL: 22.2 ± 3.83, COIL: 28.60 ± 6.27; P = 0.04), triglyceride (CON: 65 ± 12.21, OIL: 71.75 ± 6.23, CHOL: 244.2 ± 44.45, COIL: 775.6 ± 105.07; P < 0.001), and MDA between groups (CON: 0.57 ± 0.10, OIL: 0.63 ± 0.15, CHOL: 5.62 ± 0.18, COIL: 2.06 ± 0.64; P < 0.001). The comparison of CHOL and the COIL groups showed a higher mean of malondialdehyde (MDA) in group CHOL (4.47 ± 0.28 vs 1.1 ± 0.6; P < 0.001). Aortic lesion was not observed in CON and OIL groups. Aortic lesion degree was significantly lower in the COIL group compared to the CHOL (2.4 ± 0.6 vs 3.66 ± 0.33; P = 0.02). These findings showed the preventive effect of olive oil on atherosclerosis development. However, it is independent of the plasma lipoprotein effect, and olive oil probably acts on arteries directly.

Neuraminidases 1 and 3 Trigger Atherosclerosis by Desialylating Low-Density Lipoproteins and Increasing Their Uptake by Macrophages.

BackgroundChronic vascular disease atherosclerosis starts with an uptake of atherogenic modified low‐density lipoproteins (LDLs) by resident macrophages, resulting in formation of arterial fatty streaks and eventually atheromatous plaques. Increased plasma sialic acid levels, increased neuraminidase activity, and reduced sialic acid LDL content have been previously associated with atherosclerosis and coronary artery disease in human patients, but the mechanism underlying this association has not been explored.Methods and ResultsWe tested the hypothesis that neuraminidases contribute to development of atherosclerosis by removing sialic acid residues from glycan chains of the LDL glycoprotein and glycolipids. Atherosclerosis progression was investigated in apolipoprotein E and LDL receptor knockout mice with genetic deficiency of neuraminidases 1, 3, and 4 or those treated with specific neuraminidase inhibitors. We show that desialylation of the LDL glycoprotein, apolipoprotein B 100, by human neuraminidases 1 and 3 increases the uptake of human LDL by human cultured macrophages and by macrophages in aortic root lesions in Apoe−/− mice via asialoglycoprotein receptor 1. Genetic inactivation or pharmacological inhibition of neuraminidases 1 and 3 significantly delays formation of fatty streaks in the aortic root without affecting the plasma cholesterol and LDL levels in Apoe−/− and Ldlr−/− mouse models of atherosclerosis.ConclusionsTogether, our results suggest that neuraminidases 1 and 3 trigger the initial phase of atherosclerosis and formation of aortic fatty streaks by desialylating LDL and increasing their uptake by resident macrophages.

SAT-001 Supra-Physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy

Supra-physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy The impact of testosterone on the cardiovascular system is controversial and concerns have been raised in regard to the safety of testosterone replacement therapy (TTh) in hypogonadal men with cardiovascular disease. We have examined the effects of supra-physiological concentrations of testosterone upon aortic fatty streak formation in high-fat diet-fed testicular feminized (Tfm) mice, which exhibit non-functional androgen receptors (AR) and low circulating testosterone levels. Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received fortnightly intramuscular injections of either saline (Tfm, n=8, XY, n=8), 10uL of 250mg/mL testosterone alone (Tfm, n=8, XY, n=8), or in conjunction with either a 30uL intramuscular injection of 50mg/ml estrogen receptor-alpha antagonist fulvestrant (Tfm, n=8), or with 10mg/kg/day of aromatase inhibitor anastrazole in drinking water (Tfm, n=7). Cardiac tissue mRNA was analysed by qPCR for markers of hypertrophy (ANP, BNP, alpha-actin, MYH7, Gsk3-beta, SM22-alpha). A significant reduction in aortic fatty streak formation was observed in Tfm mice receiving supra-physiological testosterone compared to those receiving saline; 1.25+0.36% versus 2.85+0.37% respectively (p<0.01). No significant increase in aortic lipid deposition was observed in XY littermates administered supra-physiological testosterone compared to those receiving saline; 0.22+0.13% versus 0.32+0.12% respectively (p=ns). Aortic fatty streak formation in Tfm mice receiving supra-physiological testosterone in conjunction with fulvestrant or anastrazole was similar to that observed in Tfm mice receiving supra-physiological testosterone therapy alone; 0.71+0.18% and 1.09+0.81% respectively versus 1.25+0.36% (both p=ns) indicating non-genomic actions of testosterone. Hypertrophic markers and heart weights were elevated in XY littermates receiving supra-physiological testosterone but not in Tfm mice compared to placebo suggesting AR-dependent actions. This evidence suggests that supra-physiological levels of testosterone protect against diet induced aortic atheroma formation, at least in part, via non-genomic mechanisms but incur increased cardiovascular risk by potentially inducing cardiac hypertrophy via AR-dependent actions. Dose titration to physiological levels and careful monitoring of patients throughout treatment is key to eliciting the beneficial cardiovascular effects of TTh in hypogonadal men.

Anti-Atherosclerotic Effect of a Polyphenol-Rich Ingredient, Oleactiv®, in a Hypercholesterolemia-Induced Golden Syrian Hamster Model.

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv®, an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv® is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of fruit and vegetables commonly consumed within the Mediterranean diet. A total of 21 Golden Syrian hamsters were divided into three groups. The standard group (STD) was fed a normolipidemic diet for 12 weeks, while the control group (CTRL) and Oleactiv® goup (OLE) were fed a high-fat diet. After sacrifice, the aortic fatty streak area (AFSA), plasmatic total cholesterol (TC), high-density lipoproteins (HDL-C), non-HDL-C and triglycerides (TG), were assessed. The cholesterol efflux capacity (CEC) of hamster plasma was quantified using a radiolabeled technique in murine macrophages J774. OLE administration induced a significant reduction of AFSA (−69%, p < 0.0001). Hamsters of the OLE group showed a significant decrease of both non-HDL-C (−173 mmol/L, p < 0.05) and TG (−154 mmol/L, p < 0.05). Interestingly, OLE induced a significant increase of total CEC (+17,33%, p < 0,05). Oleactiv® supplementation prevented atheroma development and had positive effects on the lipid profile of hypercholesterolemic hamsters. The increased CEC underlines the anti-atherosclerotic mechanism at the root of the atheroma reduction observed.

Chronic whole-body heat treatment relieves atherosclerotic lesions, cardiovascular and metabolic abnormalities, and enhances survival time restoring the anti-inflammatory and anti-senescent heat shock response in mice

Unhealthy lifestyle persistently feeds forward inflammation in metabolic organs thus imposing senescence-associated secretory phenotype (SASP), as observed in obesity and type 2 diabetes. However, SASP blocks physiological resolution of inflammation by suppressing the anti-inflammatory and anti-senescent heat shock (HS) response, i.e., the gene program centered in heat shock factor-1 (HSF1)-dependent expression heat shock proteins (HSPs). As SASP-inducing factors are not removed, leading to the perpetuation of inflammation, we argued that SIRT1-HSF1-HSP axis might also be suppressed in atherosclerosis, which could be reversible by heat treatment (HT), the most powerful HS response trigger. LDLr−/− adult mice were fed on high-fat/high-cholesterol diet from the age of 90 days until the end of study (age of 270 days). After 120 days under atherosclerotic diet, the animals were submitted to either whole-body HT (n = 42; 40 °C) or sham (n = 59; 37 °C) treatment (15 min/session), under anesthesia, once a week, for 8 weeks, being echographically and metabolically monitored. Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal (LDLr+/+; n = 25) healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, HT completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of TG, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose and insulin resistance while rising HDL-cholesterol levels. HT also decreased body weight gain, visceral fat, cellular infiltration and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance (Tei) indices. Remarkably, heat-treated mice stopped dying after the third HT session (= 8 human years), suggesting a curative effect. Therefore, evolution of atherosclerosis is associated with suppression of the anti-inflammatory and anti-senescent SIRT1-HSF1-HSP molecular axis, which is refreshed by chronic heat treatment.

Erythrocyte Efferocytosis by the Arterial Wall Promotes Oxidation in Early-Stage Atheroma in Humans.

Since red blood cells (RBCs) are the predominant cellular blood component interacting with the arterial wall, we explored the role of RBCs efferocytosis by vascular smooth muscle cells (vSMCs) in the initiation of human atheroma. The comparison of human healthy aortas with aortic fatty streaks or fibroatheromas revealed that RBC angiophagy is implicated from the earliest stages of atherogenesis, as documented by the concomitant detection of redox-active iron, hemoglobin, glycophorin A, and ceroids. RBCs infiltration in the arterial wall was associated with local lipid and protein oxidation, as well as vascular response (expression of heme oxygenase-1 and of genes related to iron metabolism as well as those encoding for phagocytosis). These effects were recapitulated in vitro when vSMCs were co-cultured with phosphatidyl-exposing senescent (s) RBCs but not with fresh RBCs. VSMCs engulfing sRBC increased their intracellular iron content, accumulated hemoglobin, lipids, and activated their phagolysosomes. Strikingly, injections of sRBCs into rats promoted iron accumulation in the aortic wall. In rabbits, hypercholesterolemia increased circulating senescent RBCs and induced the subendothelial accumulation of iron-rich phagocytic foam cells. RBCs bring cholesterol and iron/heme into the vascular wall and interact with vSMCs that phagocytize them. This study presents a previously unforeseen mechanism of plaque formation that implicates intimal RBC infiltration as one of the initial triggers for foam cell formation and intimal oxidation. Pathogenic effects exerted by several metabolic and hemodynamic factors may rely on their effect on RBC biology, thereby impacting how RBCs interact with the vascular wall.

Baccaurea angulata fruit juice reduces atherosclerotic lesions in diet-induced Hypercholesterolemic rabbits

BackgroundAtherosclerosis is the most common disease of large and medium-sized arteries linked to oxidative stress, dyslipidemia as well as chronic inflammation. The aim of this study was to evaluate the potential health benefits of Baccaurea angulata (BA) fruit juice on the aorta of diet-induced hypercholesterolemic rabbits, to detect an accumulation of fatty streak and evaluate the percentage of atherosclerotic lesion accrued.MethodsThirty-five healthy male adults New Zealand White rabbits were assigned to seven different groups. Four groups were fed 1% cholesterol diet and 0, 0.5, 1.0, and 1.5 mL of BA fruit juice per kg of rabbit daily (atherogenic groups), while the other three groups were fed commercial rabbit pellet and 0, 0.5, and 1.0 mL of juice per kg of rabbit daily (normocholesterolemic groups) for 90 days. The thoracic and abdominal aorta between the heart origin and bifurcation into iliac arteries of all the rabbits were carefully removed and analyzed accordingly.ResultsThe supplementation of the high-cholesterol diet of hypercholesterolemic rabbits with only 0.5 mL BA/kg rabbit per day significantly (p < 0.001) improved aortic lipid profile, attenuated aortic fatty streak development and reduced intima thickening. Higher BA doses used (1.0 and 1.5 mL/kg rabbit per day) also significantly (p < 0.001) decreased further the development of aortic fatty streaks, reduced the thickening of the tunica intima layer and preserved endothelial healing following arterial injury.ConclusionTherefore, BA fruit is a potential novel functional food with effective anti-inflammatory, anti-atherogenic and hypocholesterolemic activities.

Anti-atherosclerosis effect of pine nut oil in high-cholesterol and high-fat diet fed rats and its mechanism studies in human umbilical vein endothelial cells

The objective of this study was to determine the anti-atherosclerotic effects of pine nut oil in rats fed a high-cholesterol and high-fat diet (HCHF). Using a randomized block design, Sprague-Dawley rats were divided into 5 groups and fed experimental diets for 6 weeks (normal diet, HCHF, HCHF+7 or 15% pine nut oil, HCHF+simvastatin). This study shows that markers of atherosclerosis, such as increased liver thiobarbituric acid reactive substance levels, aortic fatty streak area, and low-density lipoprotein cholesterol concentrations, were lower in the HCHF plus pine nut oil groups than in the HCHF group. Conversely, positive cardiovascular indicators, such as increased paraoxonase activity and high-density lipoprotein cholesterol concentrations, were higher in HCHF plus pine nut oil groups than in the HCHF group. This study suggests that pine nut oil improves atherosclerotic markers and could be used as a functional ingredient in the food industry to promote cardiovascular health.

Antiobesity and Vasoprotective Effects of Resveratrol in ApoE-Deficient Mice

This study was performed to investigate the hypolipidemic, antiobese, and antiatherogenic effects of resveratrol in apoE-deficient mice fed an atherogenic diet (20% fat and 1% cholesterol). These animals were fed an atherogenic diet containing 0.02% lovastatin (w/w) or 0.02% resveratrol (w/w) for 12 weeks. Resveratrol and lovastatin supplementation significantly reduced either the body weight or epididymal fat weight without altering the food intake and food efficiency ratio. Resveratrol significantly decreased the plasma total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) concentrations, apoB/apoA-I ratio, hepatic cholesterol, and triglyceride (TG) contents, whereas significantly it increased the plasma HDL-C concentration compared with the control and lovastatin groups. Plasma and hepatic TG and plasma apoB levels were significantly lower in both the lovastatin and resveratrol groups than in the control group without altering the plasma apoA-I concentration. Both resveratrol and lovastatin significantly decreased hepatic fatty acid and TG synthesis, whereas they increased fatty acid oxidation (β-oxidation) except for the carnitine palmitoyltransferase activity compared with the control group. However, there was no difference in hepatic 3-hydroxyl-3-methylglutaryl-CoA reductase activity among the groups, although hepatic acyl-CoA: cholesterol acyltransferase activity was significantly lower in the lovastatin groups than in the control group. In epididymal adipose tissue, resveratrol supplementation led to an increase in β-oxidation and decrease in TG synthesis, compared with the control group. Tissue morphology revealed that there were dramatic decreases in hepatic lipid droplets and aortic fatty streaks by resveratrol and lovastatin supplementation. This study demonstrates that resveratrol exerts not only antiobesity and hypolipidemic effects, but also protective effects for the liver and aorta through the modulation of lipid metabolism in both the liver and white adipose tissues.

Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo

Lectin-like oxLDL receptor-1 (LOX-1) mediates the uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells and macrophages. However, the different atherogenic potential of LOX-1-mediated endothelial and macrophage oxLDL uptake remains unclear. The present study was designed to investigate the in vivo role of endothelial LOX-1 in atherogenesis. Endothelial-specific LOX-1 transgenic mice were generated using the Tie2 promoter (LOX-1TG). Oxidized low-density lipoprotein uptake was enhanced in cultured endothelial cells, but not in macrophages of LOX-1TG mice. Six-week-old male LOX-1TG and wild-type (WT) mice were fed a high-cholesterol diet (HCD) for 30 weeks. Increased reactive oxygen species production, impaired endothelial nitric oxide synthase activity and endothelial dysfunction were observed in LOX-1TG mice as compared with WT littermates. LOX-1 overexpression led to p38 phosphorylation, increased nuclear factor κB activity and subsequent up-regulation of vascular cell adhesion molecule-1, thereby favouring macrophage accumulation and aortic fatty streaks. Consistently, HCD-fed double-mutant LOX-1TG/ApoE(-/-) displayed oxidative stress and vascular inflammation with higher aortic plaques than ApoE(-/-) controls. Finally, bone marrow transplantation experiments showed that endothelial LOX-1 was sufficient for atherosclerosis development in vivo. Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosis.

Deep Sea Water Modulates Blood Pressure and Exhibits Hypolipidemic Effects via the AMPK-ACC Pathway: An in Vivo Study

Deep sea water (DSW), originally pumped from the Pacific Rim off the coast of Hualien County (Taiwan), and its mineral constituents, were concentrated by a low-temperature vacuum evaporation system to produce a hardness of approximately 400,000 mg/L of seawater mineral concentrate. The primary composition of this seawater mineral concentrate was ionic magnesium (Mg2+), which was approximately 96,000 mg/L. Referring to the human recommended daily allowance (RDA) of magnesium, we diluted the mineral concentrate to three different dosages: 0.1 × DSW (equivalent to 3.75 mg Mg2+/kg DSW); 1 × DSW (equivalent to 37.5 mg Mg2+/kg DSW); and 2 × DSW (equivalent to 75 mg Mg2+/kg DSW). Additionally, a magnesium chloride treatment was conducted for comparison with the DSW supplement. The study indicated that 0.1 × DSW, 1 × DSW and 2 × DSW decreased the systolic and diastolic pressures in spontaneous hypertensive rats in an eight-week experiment. DSW has been shown to reduce serum lipids and prevent atherogenesis in a hypercholesterolemic rabbit model. Our results demonstrated that 1 × DSW and 2 × DSW significantly suppressed the serum cholesterol levels, reduced the lipid accumulation in liver tissues, and limited aortic fatty streaks. These findings indicated that the antiatherogenic effects of DSW are associated with 5′-adenosine monophosphate-activated protein kinase (AMPK) stimulation and the consequent inhibition of phosphorylation of acetyl-CoA carboxylase (ACC) in atherosclerotic rabbits. We hypothesize that DSW could potentially be used as drinking water because it modulates blood pressure, reduces lipids, and prevents atherogenesis.

Curcumin modulation of atherosclerosis and hepatosteatosis in LDLr−/− mice

Limited animal studies reported that curcumin (Cur), a bioactive component of turmeric spice, suppresses atherosclerosis, an inflammatory disease of arteries, but the mechanism for these effects is largely unknown. LDLr−/ − mice were fed high fat (HF) diet supplemented with increasing Cur doses (500, 1,000, 1,500 mg/kg diet) for 16 wks. Cur reduced BW and fat gain although fecal fat excretion was less than control's suggesting increased catabolism. Medium dose Cur diet (1,000 mg/kg) significantly reduced aortic fatty streaks and suppressed IL‐6 and MCP‐1 expression in aortas, but high dose diet (1,500 mg/kg) had adverse effect on these parameters and increased plasma levels of several inflammatory cytokines including IL‐6, IL‐10, IL‐12. This U‐shaped trend was also present when aortic roots were examined for fatty lesions, fibrotic deposits, FABP‐4/aP2 and VCAM‐1 expression. Of note, Cur at high dose suppressed hepatosteatosis, reduced fibrotic tissue, and preserved liver glycogen levels. While complex mechanisms are involved in Cur suppression of HF diet‐induced atherosclerosis and obesity, Cur suppression of aP2 and VCAM‐1 expression in aortic root lesions and aP2 expression in macrophages along with reduction of inflammatory cytokines provide an insight to the potential mechanism by which Cur suppresses atherogenesis and obesity. NIFA/USDA grant #2010–65200‐20395 &amp;USDA contract #58–1950‐0–014.

Influence of different particle processing on hypocholesterolemic and antiatherogenic activities of yam (Dioscorea pseudojaponica) in cholesterol‐fed rabbit model

Nanoparticle processing is implicated in enhancing bioactive or nutritional compound release from raw foods. The aim of the present study was to evaluate whether different particle processing might affect the lipid-lowering activity of Dioscorea pseudojaponica (DP) and to investigate whether DP could be a potential functional food for prevention of atherogenesis. Its possible molecular mechanisms were also evaluated. The results indicated that 50 mesh-size DP (50 mesh DP) particles exhibited stronger effects than nanoscale DP (nano DP) particles in terms of lowering the level of serum cholesterol as well as reducing the extent of fatty liver and aortic fatty streak. Moreover, both DP particle types, particularly 50 mesh DP, significantly activated AMPK (5'-adenosine monophosphate-activated protein kinase) and deactivated ACC (acetyl-CoA carboxylase), as demonstrated by the increased levels of both enzymes in their phosphorylated form. Coincidently, high-performance liquid chromatography (HPLC) analysis showed a higher content (P < 0.01) of dioscin, a known lipid-lowering compound, in 50 mesh DP than in nano DP. These results suggest that improper processing conditions will lead to the decomposition of bioactive components in yam. They also demonstrate for the first time that the lipid-lowering mechanisms of DP may occur through the AMPK-ACC pathway.

β-Glucan Fiber from Spent Brewer’s Yeast Reduces Early Atherosclerosis Greater Than Psyllium in Hypercholesterolemic Syrian Golden Hamsters

β-Glucans, mostly from oats, have been shown to reduce blood concentrations of total and LDL-cholesterol in animals and humans. After processing, spent brewer’s yeast, a by-product of the fermentation process, contains 85% - 90% β-glucans. The purpose of this study was to evaluate the effect of yeast-derived β-glucan fiber on plasma lipids and early atherosclerosis development in hamsters consuming a semi-purified hypercholesterolemic diet (HCD). Animals were fed either the HCD or the HCD containing psyllium or β-glucan fiber from yeast for 12 weeks. Both the psyllium and β-glucan fiber from yeast showed significant decreases in plasma total cholesterol, non-HDL-C, triacylglycerol, and aortic fatty streak area when compared to the HCD. Also, the β-glucan fiber from yeast had significantly less aortic fatty streak area compared to the psyllium diet. Findings from this study show that while both β-glucan fiber from yeast and psyllium produced similar reductions in plasma lipid and lipoprotein concentrations, the β-glucan fiber from yeast prevented the development early atherosclerosis better than psyllium in the hamsters.

Effect of Testosterone on Inflammatory Markers in the Development of Early Atherogenesis in the Testicular-Feminized Mouse Model

Background. Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis. Aim. We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis. Methods. Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates. Results. A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CX3CL1) and its receptor (CX3CR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status. Conclusion. These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.

Experimentally-Induced Metabolic Acidosis Does not Alter Aortic Fatty Streak Formation in High-Cholesterol Fed Rabbits.

Cardiovascular disease causes a major clinical problem in patients with end stage renal disease. Since metabolic acidosis is very common in patients with end stage renal disease, we aimed to investigate the effect of experimentally-induced metabolic acidosis on serum lipid profile and aortic fatty streak (FS) formation in normal and high-cholesterol fed rabbits. Twenty-four male rabbits were divided into four groups (n=6 each): (1) normal diet (ND): (2) hypercholesterolemic diet (HCD) (1%): (3) ND plus acidemic diet: (4) HCD plus acidemic diet. Metabolic acidosis was induced by adding 0.75% NH4Cl in drinking water. After 4 weeks, blood samples were taken and thoracic aortae were dissected for histological examinations. Results showed that in the animals who received NH4Cl, metabolic acidosis was successfully induced. Serum total cholesterol and low density lipoprotein (LDL) concentrations in HCD groups were significantly higher than ND groups (P<0.05) and acidosis did not significantly change serum lipid levels neither in ND nor in HCD animals (P>0.05). Histological examination of aortae showed higher mean average grades of pathological evaluation in HCD than ND groups (2.1±0.16 vs. 0±0; P<0.05). Acidosis did not further increase FS formation in HCD groups (P >0.05). In this model of experimentally-induced metabolic acidosis, acidosis could not increase FS formation in HCD animals and it seems that it does not interfere in progression of atherosclerosis process.

Vineatrol and Cardiovascular Disease: Beneficial Effects of a Vine-Shoot Phenolic Extract in a Hamster Atherosclerosis Model

We evaluated the effect of the intake of a grapevine-shoot phenolic extract (Vineatrol 30) on early atherosclerosis in hamsters fed a hyperlipidic diet. Golden Syrian hamsters received for 13 weeks either a standard diet, a high-fat (HF) diet, or the HF diet plus Vineatrol 30 at 0.04, 0.2, or 1.0 mg/(kg body weight/d). We measured plasma lipids and glucose, insulin, leptin and adiponectin, as well as liver TNF-α and IL-6 levels. Oxidative stress was assessed by measuring plasma paraoxonase activity (PON) and liver superoxide anion production (O(2)(•-)). The aortic fatty streak area (AFSA) was also determined. In comparison with HF group, we demonstrated that the highest dose of Vineatrol 30 was capable of decreasing AFSA (67%), insulinemia (40%), and leptinemia (8.7%), which were increased by the HF diet. We also showed increased O(2)(•-) production (35%) and a rise in levels of the liver proinflammatory cytokines TNF-α (22%) and IL-6 (21%), accompanied by a fall in PON activity (56%) due to the HF diet versus the standard diet. In contrast, except plasma adiponectin levels that are not changed, Vineatrol 30 treatment lowered AFSA (67%), O(2)(•-) production (36%), insulin resistance (42%), leptinemia (9%), liver TNF-α (18%) and IL-6 (15%), while it rose PON activity (29%). These findings demonstrate the preventive effects of polyphenols present in Vineatrol 30 in managing cardiovascular, metabolic, and inflammatory risk factors.

Effect of chronic L-Arginine supplementation on aortic fatty streak formation and serum nitric oxide concentration in normal and high-cholesterol fed rabbits

Several reports indicated the beneficial effects of short-term L-Arginine (L-Arg) administration on atherosclerosis processes. The aim of this study was to evaluate the effect of chronic L-Arg supplementation on serum lipid profile, aortic Fatty Streak (FS) formation, and serum Nitric oxide (NO) concentration in Normal Diet (ND) and High-Cholesterol Diet (HCD) fed rabbits. 24 male rabbits were randomly divided into four groups (n=6 in each group) (i): ND for seven months; (ii): ND for 1 month plus ND + L-Arg for six months; (iii): HCD (1%) for 1 month plus HCD (0.5%) for six months; (iv): HCD (1%) for 1 month plus HCD (0.5%) + L-Arg for six months. At the end of the study, histological evaluation of aortic FS formation was performed. Blood samples were taken for serum lipid profile and NO concentrations. L-Arg did not change serum total cholesterol, triglyceride, LDL and LDL/HDL ratio in normal and hypercholesterolemic rabbits (p>0.05). Histological examination of thoracic aortae revealed that the HCD group had higher FS formation compared to the ND group (2.1 ± 0.16 vs. 0 ± 0; respectively; p<0.05) and L-Arg supplementation did not attenuate FS formation in the HCD group (1.93 ± 0.17 compare to 2.1 ± 0.16; p>0.05). Serum NO level in the HCD group was higher than ND groups (p<0.05). Chronic L-Arg supplementation did not alter serum NO concentration either in the hypercholesterolemic or in the ND group (p>0.05). It seems that chronic L-Arg supplementation does not have beneficial effects on aortic fatty streak formation, serum lipids and NO concentrations in this model of experimental hypercholesterolemia.

CHEMICAL INDICES, ANTIOXIDANT ACTIVITY AND ANTI-INFLAMMATORY EFFECT OF EXTRACTS OF THE MEDICINAL RICE “NJAVARA” AND STAPLE VARIETIES: A COMPARATIVE STUDY

Chemical indices, antioxidant and anti-inflammatory activity of extracts of bran of medicinal rice – Njavara “black glumed” type (NBb) and its rice (NBr), were studied in comparison with bran and rice of staple varieties: Sujatha and Palakkadan Matta. Total oryzanol, phenolic, flavonoid, proanthocyanidin and phytate contents of NBb (1.84 mg/g, 27.16 mg of gallic acid/g, 4.50 mg of quercetin/g, 0.98 mg of catechin/g and 8.77 mg/g dry weight of bran, respectively) were higher compared with NBr and staple varieties. NBb showed greater reducing power and significantly higher scavenging activity with 2, 2-diphenyl-1-picryl hydrazyl radical, superoxide and hydrogen peroxide with values of concentration of NBb required to scavenge 50% of respective radicals (IC50): 84.66, 203.16 and 73.55 µg/mL, respectively. The anti-inflammatory effect (in vivo) of NBb was 83.3%, whereas NBr and staple varieties showed activity in the range 16–66%. The higher oryzanol content, chemical indices, antioxidant and anti-inflammatory activity for Njavara compared with staple varieties corroborates with its medicinal use in Ayurveda. PRACTICAL APPLICATIONS Medicinal plants are a source of antioxidants and bioactive compounds responsible for the prevention of oxidative stress that leads to many degenerative diseases and conditions. The present study indicates that the extracts of “Njavara” (black glumed), a medicinal rice variety, contains significant amounts of oryzanols, phenolic acids, flavonoids, proanthocyanidins and phytic acid compared with staple varieties. These extracts are potential free radical scavengers and have anti-inflammatory effect compared with staple varieties. Njavara, identified as a source of bioactive compounds, can be consumed as a health food in addition to its medicinal uses; thus, benefiting consumers. Higher oryzanol content in Njavara is beneficial for lowering plasma cholesterol, reducing platelet aggregation, nerve imbalances and aortic fatty streak formation. Higher antioxidants in Njavara are also beneficial against the diseases initiated by free radicals. These promising results also open up newer areas of research for developing improved varieties of rice containing more bioactive compounds.