Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model, the SR-B1ΔCT/LDLR KO mouse.

BACKGROUND AND AIMS: There are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse. METHODS: SR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later. RESULTS: When six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease. For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t-test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t-test, n = 8, p = 0.003). CONCLUSIONS: This new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease.

Silicon-enriched meat positively improves plasma lipidaemia and lipoproteinaemia, LDLr, and insulin capability and the signalling pathway induced by an atherogenic diet in late-stage type 2 diabetes mellitus rats.

The impact of silicon as a functional ingredient in restructured meat (RM) on lipoprotein composition, metabolism, and oxidation on type 2 diabetes mellitus (T2DM) markers has never been studied. This study aims to evaluate the effect of silicon-enriched-meat consumption on lipidaemia, lipoprotein profile and metabolism, plasma arylesterase, and TBARS and their relationships with glycaemia, insulinaemia, and insulin-signaling markers in late-stage-T2DM rats fed a high-saturated-fat-high-cholesterol (HSFHC) diet. Saturated-fat diets with or without added cholesterol were formulated by mixing a 70% purified diet with 30% freeze-dried RM with or without added silicon. Three groups of seven Wistar rats each were tested. The ED group received the control RM in the framework of a high-saturated-fat diet as early-stage T2DM control. The other two groups received streptozotocin-nicotinamide administration together with the HSFHC diet containing the control RM (LD) or silicon-enriched RM (LD-Si). Scores were created to define the diabetic trend and dyslipidaemia. The ED rats showed hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia, and triglyceride-rich-VLDLs, suggesting they were in early-stage T2DM. LD rats presented hyperglycaemia, hypoinsulinaemia, and reduced HOMA-beta and insulin signaling markers typical of late-stage T2DM along with hypercholesterolaemia and high amounts of beta-VLDL, IDL, and LDL particles and low arylesterase activity. All these markers were significantly (p < 0.05) improved in LD-Si rats. The diabetic trend and diabetes dyslipidaemia scores showed a high and significant correlation (r = 0.595, p < 0.01). Silicon-enriched-meat consumption counterbalances the negative effects of HSFHC diets, functioning as an active hypolipemic, antioxidant, and antidiabetic dietary ingredient in a T2DM rat model, delaying the onset of late-stage diabetes.

Oridonin supplementation in rabbits may help to improve the outcome of induced atherosclerosis via autophagy induction.

BACKGROUND AND AIM: Inflammation plays a crucial role in the development of atherosclerotic plague. Oridonin is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens. It is a natural terpenoids that is known as a strong anti-inflammatory supplement by acting as a potent inhibitor of the TXNIP/NLRP3 pathway. Hence, it can reduce the severity of inflammation and improve the outcome of atherosclerotic changes. This study aims to evaluate the anti-inflammatory effects of oridonin in the progression of atherosclerotic plague in rabbits. METHODS: Sixty-three male rabbits were included. The rabbits were randomly assigned to one of the three study groups (21 rabbits in each group), normal control diet (NC) fed normal diet for 8 weeks, atherogenic control (AC) fed atherogenic diet (2% cholesterol-enriched diet) for 8 weeks, and oridonin treated group (OT) fed atherogenic diet (2% cholesterol-enriched diet) with oridonin (purity 94%, Sigma-Aldrich, USA) at 20 mg/kg orally daily for 8 weeks. After the end of the study, blood and tissue samples were collected for analysis of various markers of inflammation and atherosclerotic plaque progression. RESULTS: Serum lipids showed a statistically significant improvement in terms of reduction in total cholesterol and low-density lipoprotein (LDL) in the OT group compared to the AC group. This was associated with a significant reduction in serum F2-isoprostane (marker of inflammation) and LC3B (marker of tissue autophagy) between the OT group compared to the AC group. There was also a significant reduction in NLRP3 inflammasome RNA expression in OT group, P<0.001. CONCLUSIONS: In animal model, with atherogenic diet, oridonin supplementation can significantly improve the outcome of atherosclerosis by its strong anti-inflammatory action.

Therapeutic effects of resveratrol and Omega-3 in mice atherosclerosis: focus on histopathological changes.

BACKGROUND: Resveratrol and omega-3 have been shown to prevent atherosclerosis. However, histopathological changes and their comparison have not been studied well. This study investigated the therapeutic effects of resveratrol and omega-3 in experimental atherosclerosis of mice. METHODS: We divided sixty 6-week-old male C57BL/6 mice into six groups and followed for 10 weeks: (1) standard diet, (2) atherogenic diet, (3) atherogenic diet along with resveratrol from the start of the sixth week, (4) atherogenic diet along with omega-3 from the start of the sixth week, (5) standard diet along with resveratrol from the start of the sixth week, (6) standard diet along with omega-3 from the start of the sixth week. RESULTS: The mice fed on an atherogenic diet had a larger fat area and a thicker aortic wall thickness than mice fed on a standard diet. The use of omega-3 and resveratrol in the mice with an atherogenic diet resulted in a significantly reduced fat area (p-value = 0.003), and resveratrol had a significantly higher effect. Omega-3 or resveratrol induced a significant reduction in aortic wall thickness in mice on an atherogenic diet, and there was no significant difference between them. Among the mice with a standard diet, this study did not observe any significant changes in the fat area or the aortic wall thickness with the consumption of omega-3 or resveratrol. CONCLUSIONS: Resveratrol and omega-3 had a regressive and therapeutic role in atherosclerosis, with a more significant effect in favor of resveratrol.

Cornelian Cherry (Cornus mas L.) Iridoid and Anthocyanin-Rich Extract Reduces Various Oxidation, Inflammation, and Adhesion Markers in a Cholesterol-Rich Diet Rabbit Model.

Atherogenesis leads to the development of atherosclerosis, a progressive chronic disease characterized by subendothelial lipoprotein retention and endothelial impairment in the arterial wall. It develops mainly as a result of inflammation and also many other complex processes, which arise from, among others, oxidation and adhesion. Cornelian cherry (Cornus mas L.) fruits are abundant in iridoids and anthocyanins-compounds with potent antioxidant and anti-inflammatory activity. This study aimed to determine the effect of two different doses (10 mg and 50 mg per kg of body weight, respectively) of iridoid and anthocyanin-rich resin-purified Cornelian cherry extract on the markers that are important in the progress of inflammation, cell proliferation and adhesion, immune system cell infiltration, and atherosclerotic lesion development in a cholesterol-rich diet rabbit model. We used biobank blood and liver samples that were collected during the previous original experiment. We assessed the mRNA expression of MMP-1, MMP-9, IL-6, NOX, and VCAM-1 in the aorta, and the serum levels of VCAM-1, ICAM-1, CRP, PON-1, MCP-1, and PCT. The application of the Cornelian cherry extract at a dose of 50 mg/kg bw resulted in a significant reduction in MMP-1, IL-6, and NOX mRNA expression in the aorta and a decrease in VCAM-1, ICAM-1, PON-1, and PCT serum levels. The administration of a 10 mg/kg bw dose caused a significant decrease in serum ICAM-1, PON-1, and MCP-1. The results indicate the potential usefulness of the Cornelian cherry extract in the prevention or treatment of atherogenesis-related cardiovascular diseases, such as atherosclerosis or metabolic syndrome.

Wheat Germ Supplementation Reduces Inflammation and Gut Epithelial Barrier Dysfunction in Female Interleukin-10 Knockout Mice Fed a Pro-Atherogenic Diet.

BACKGROUND: Mice lacking IL-10 are prone to gut inflammation. Additionally, decreased production of short-chain fatty acids (SCFAs) plays a significant role in the high-fat (HF) diet-induced loss of gut epithelial integrity. We have previously shown that wheat germ (WG) supplementation increased ileal expression of IL-22, an important cytokine in maintaining gut epithelial homeostasis. OBJECTIVES: This study investigated the effects of WG supplementation on gut inflammation and epithelial integrity in IL-10 knockout mice fed a pro-atherogenic diet. METHODS: Eight-week-old female C57BL/6 wild type mice were fed a control diet (10% fat kcal), and age-matched knockout mice were randomly assigned to 1 of 3 diets (n = 10/group): control, high-fat high-cholesterol (HFHC) [(43.4% fat kcal (∼49% saturated fat, 1% cholesterol)], or HFHC + 10% WG (HFWG) for 12 wk. Fecal SCFAs and total indole, ileal, and serum proinflammatory cytokines, gene or protein expression of tight junctions, and immunomodulatory transcription factors were assessed. Data were analyzed by 1-way ANOVA, and P < 0.05 was considered statistically significant. RESULTS: Fecal acetate, total SCFAs, and indole increased (P < 0.05) by at least 20% in HFWG compared with the other groups. WG increased (P < 0.0001, 2-fold) ileal Il22 (interleukin 22) to Il22ra2 (interleukin 22 receptor, alpha 2) mRNA ratio and prevented the HFHC diet-mediated increase in ileal protein expression of indoleamine 2,3 dioxygenase and pSTAT3 (phosphorylated signal transducer and activator of transcription 3). WG also prevented the HFHC diet-mediated reduction (P < 0.05) in ileal protein expression of the aryl hydrocarbon receptor and the tight junction protein, zonula occludens-1. Serum and ileal concentrations of the proinflammatory cytokine, IL-17, were lower (P < 0.05) by at least 30% in the HFWG group than in the HFHC group. CONCLUSIONS: Our findings demonstrate that the anti-inflammatory potential of WG in IL-10 KO mice consuming an atherogenic diet is partly attributable to its effects on the IL-22 signaling and pSTAT3-mediated production of T helper 17 proinflammatory cytokines.

Adding Modified Buckwheat Sprouts to an Atherogenic Diet - the Effect on Selected Nutritional Parameters in Rats.

The germinated seeds of many plants are a natural source of substances that can be used to supplement food and increase its functionality. The seeds' metabolism may be modified during germination to produce specific health-promoting compounds. Fagopyrum esculentum Moench is a rich source of nutrients. Buckwheat seeds modified during germination may be helpful as an additive to new functional food products with anti-atherogenic properties. However, their effect and safety should be assessed in in vivo studies. The aim of the study was to evaluate the effect that adding modified buckwheat sprouts (Fagopyrum esculentum Moench) to an atherogenic (high-fat) diet has on the morphology and digestibility parameters of rats. Buckwheat seeds were modified by adding the probiotic strain of the yeast Saccharomyces cerevisiae var. boulardii. The study was carried out on 32 Wistar rats, and digestibility and blood counts were assessed during the experiment. There was no evidence of an adverse effect on the animals' weight gain and nutritional efficiency. However, the influence of diets with freeze-dried buckwheat sprouts on digestibility and morphological parameters was noticed. Fat digestibility registered a statistically significant decrease in the groups fed a high-fat diet with the addition of sprouts. The study shows a new direction in the use of buckwheat sprouts.

Effects of atherogenic diet supplemented with fermentable carbohydrates on metabolic responses and plaque formation in coronary arteries using a Saddleback pig model.

Fermentable carbohydrates are gaining interest in the field of human nutrition because of their benefits in obesity-related comorbidities. The aim of this study was to investigate the influence of fermentable carbohydrates, such as pectin and inulin, in an atherogenic diet on metabolic responses and plaque formation in coronary arteries using a Saddleback pig model. Forty-eight healthy pigs aged five months were divided into four feeding groups (n = 10) and one baseline group (n = 8). Three feeding groups received an atherogenic diet (38% crisps, 10% palm fat, and 2% sugar with or without supplementation of 5% pectin or inulin), and one group received a conventional diet over 15 weeks. Feed intake, weight gain, body condition score, and back fat thickness were monitored regularly. Blood and fecal samples were collected monthly to assess the metabolites associated with high cardiovascular risk and fat content, respectively. At the end of 15 weeks, the coronary arteries of the pigs were analyzed for atherosclerotic plaque formation. Independent of supplementation, significant changes were observed in lipid metabolism, such as an increase in triglycerides, bile acids, and cholesterol in serum, in all groups fed atherogenic diets in comparison to the conventional group. Serum metabolome analysis showed differentiation of the feeding groups by diet (atherogenic versus conventional diet) but not by supplementation with pectin or inulin. Cardiovascular lesions were found in all feeding groups and in the baseline group. Supplementation of pectin or inulin in the atherogenic diet had no significant impact on cardiovascular lesion size. Saddleback pigs can develop naturally occurring plaques in coronary arteries. Therefore, this pig model offers potential for further research on the effects of dietary intervention on obesity-related comorbidities, such as cardiovascular lesions, in humans.

Deficiency of B vitamins leads to cholesterol-independent atherogenic transformation of the aorta.

Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.

Effect of the Addition of Buckwheat Sprouts Modified with the Addition of Saccharomyces cerevisiae var. boulardii to an Atherogenic Diet on the Metabolism of Sterols, Stanols and Fatty Acids in Rats.

The aim of the study was to evaluate the effect of the addition of Fagopyrum esculentum Moench buckwheat sprouts modified with the addition of Saccharomyces cerevisiae var. boulardii to an atherogenic diet on the metabolism of sterols and fatty acids in rats. It was noticed in the study that the group fed with modified sprouts (HFDPRS) had a greater amount of sterols by 75.2%, compared to the group fed on an atherogenic diet (HFD). The content of cholesterol in the liver and feces was lower in the HFDPRS group than the HFD group. In the serum of the HFDPRS group, a more significant amount of the following acids was observed: C18:2 (increase by 13.5%), C20:4 (increase by 15.1%), and C22:6 (increase by 13.1%), compared to the HFDCS group. Regarding the biochemical parameters, it was noted that the group fed the diet with the addition of probiotic-rich sprouts diet had lower non-HDL, LDL-C and CRP ratios compared to the group fed the high-fat diet. The obtained results indicate that adding modified buckwheat sprouts to the diet by adding the probiotic strain of the yeast may have a significant impact on the metabolism of the indicated components in the organism.

Chronic ethanol consumption plus an atherogenic diet cause metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low-density lipoprotein receptor double-knockout mice.

BACKGROUND: Nonalcoholic steatohepatitis is the inflammatory subtype of nonalcoholic fatty liver disease with a high risk of progression to liver fibrosis. We investigated metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low-density lipoprotein receptor double-knockout (AL) mice fed a co-diet of ethanol with a low-carbohydrate-high-protein-high-fat atherogenic diet (AD) for 16 weeks. We also examined the underlying mechanisms, especially hepatic sympathetic activation, involved in the effects. METHODS: We maintained 12-week-old male AL mice on AD and a standard chow diet (SCD) with or without ethanol treatment for 16 weeks. Age-matched male C57BL/6J mice on SCD without ethanol treatment served as controls. We conducted blood biochemical, histopathological, and fluorescence immunohistochemical, and reverse transcriptase polymerase chain reaction studies. RESULTS: AL mice showed significant hyperlipidemia. AD induced increased body weight, hepatic steatosis, and hepatic damage; ethanol and the AD co-diet resulted in hepatic sympathetic activation accompanied by hepatic steatosis, lobular inflammation, bridging fibrosis, and hepatic damage. Hepatic Kupffer cells (KCs) and hepatic stellate cells (HSCs), which showed sympathetic activation, produced 4.4- to 9.4-fold more inflammatory factors (KC and KC-derived tumor necrosis factor-α, and chemokine [C-C motif] ligand 2) and 2.0- to 32.0-fold more fibrosis factors (HSC and HSC-derived transforming growth factor ß1 and collagen 1a1); all p < 0.05 vs. controls. CONCLUSIONS: We created a model of metabolic steatohepatitis with advanced liver fibrosis from coexisting hyperlipidemia and hepatic sympathetic activation in AL mice on a co-diet of ethanol and AD. KCs and HSCs became the cellular targets of hepatic sympathetic activation, which could play a role in the initiation and progression of metabolic steatohepatitis with advanced liver fibrosis.

Lactobacillus reuteri CCFM8631 Alleviates Hypercholesterolaemia Caused by the Paigen Atherogenic Diet by Regulating the Gut Microbiota.

Cardiovascular disease has one of the highest global incidences and mortality rates. Atherosclerosis is the main cause of cardiovascular disease, and hypercholesterolaemia and hyperlipidaemia are the main risk factors for the development of atherosclerosis. Decreasing serum cholesterol and triglyceride concentrations is considered to be an effective strategy to prevent atherosclerotic cardiovascular disease. Previous studies have shown that many diseases are related to gut microbiota dysbiosis. The positive regulation of the gut microbiota by probiotics may prevent or treat certain diseases. In this study, Lactobacillus reuteri CCFM8631 treatment was shown to decrease plasma total cholesterol (TC), low-density lipoprotein-cholesterol, aspartate transaminase, alanine transaminase and trimethylamine N-oxide concentrations, decrease liver TC and malondialdehyde concentrations and recover liver superoxide dismutase concentrations in mice fed a Paigen atherogenic diet. In addition, L. reuteri increased the faecal short-chain fatty acid content (acetate, propionate and butyrate), which was accompanied by an increase in the relative abundance of faecal Deferribacteres, Lachnospiraceae NK4A136 group, Lactobacillus and Dubosiella; a decrease in the relative abundance of Erysipelatoclostridium and Romboutsia and the activation of butanoate and vitamin B6 metabolism, leading to the alleviation of hypercholesterolaemia.

The beneficial effects of virgin olive oil against oxidative stress induced by hypercholesterolemia in rats

Cardiovascular disease(CVD) remains the major cause of mortality in the world, typically claiming a third of all deaths. The primary cause of CVD is atherosclerosis. Therefore, timely prevention and therapy of atherosclerosis are able to reduce the risk of the development of its clinical manifestations. Anti-atherosclerotic activity of medicinal plants mainly appears in their multiple effects.This study was carried out to evaluate the hypolipidemic activity of virgin olive oil in experimentally induced hyperlipemic Wistar. A total of 24 rats were randomly allocated to 4 equal groups and treated as follows for 50 days: (1) Normal control (NC); that were fed with a standart diet; (2) High Cholesterol Diet Control (HCD); which received high cholesterol diet for 50 days; (3) Animals receiving high cholesterol diet for 50 days, after this period the animals are fed for eight days by the standard foodand receiving by gavage virgin olive oil (HCD+VOO) and(4) Animals fed for eight days with the standard food and receiving by gavage olive oil (VOO). High Cholesterol Diet containing yolk egg and coconut oil. Results showed that olive oil caused a significant (p < 0.01) reduction in serum levels of Total Cholesterol (TC), Triglycerides (TG), Low­Density Lipoprotein Cholesterol (LDL) and Atherogenic Index Serum (AIS). The results also demonstrated a significant (p < 0.01) increase in High­Density Lipoprotein Cholesterol (HDL). Moreover, virgin olive oil induced a significant reduction in liver lipid content. On the other hand, a High cholesterol diet induced oxidative stress was measured by estimating reduced glutathione level and amount of thiobarbituric acid reactive substances (TBARS) formed as an index of lipid peroxidation in a liver and a heart. Virgin olive oil supplementation attenuated all these variations. Our observations of the study indicate that the virgin olive oil has a significant antihyperlipidemic potential.

The Influence of Plants from the Alliaceae Family on Morphological Parameters of the Intestine in Atherogenic Rats.

Bulbs from the Alliaceae family have been well-known and valued spices for thousands of years, not only for their unique flavor and aroma features, but also for their high nutritional and health-promoting values. Long-term or excessive consumption of these vegetables, especially raw garlic, can have side effects in the body (including in the digestive tract), causing a number of pathological changes in the intestinal wall; these changes lead, in turn, to its damage, dysfunction, and disorder development. Therefore, the aim of this study was to investigate the effect of the addition of freeze-dried vegetables from the Alliaceae family, i.e., garlic (Allium sativum L.), white onion, and red onion (Allium cepa L.) on the morphometric parameters (intestinal villi length, crypt depth, thickness of tunica mucosa, and the thickness of tunica muscle) of the jejunum of rats fed a semi-synthetic atherogenic diet (1% dietary cholesterol). In freeze-dried vegetables administered to rats, the contents of selected bioactive ingredients and their antioxidant potentials were determined. The effect of the onion vegetable supplements on growth parameters, serum lipid profile, plasma antioxidant potential, and the intestinal morphological parameters of rats loaded with cholesterol was determined. In an animal experiment, 30 male Wistar rats were divided into 5 diet groups, diet consumption and FER were studied. Supplementation of the atherogenic diet with vegetables improved the blood plasma lipid profiles and atherogenic indices, in a manner that was dependent on the type of supplementation used, with the best hypolipidemic and anti-atherosclerotic effects found in garlic use. The atherogenic diet, as well as the supplementation of this diet with the tested vegetables from the Alliaceae family, influenced the histological changes in the epithelium of the jejunum of rats. The damage to the intestinal mucosa was the greatest in animals fed an atherogenic diet supplemented with garlic. Bearing in mind that the desired beneficial therapeutic or prophylactic effects of onion vegetables (in particular garlic) in the course of various metabolic ailments (including atherosclerosis) are achieved during long-term supplementation, it is important to remember their possible cytotoxic effects (e.g., on the digestive tract) in order to achieve real benefits related to the supplementation with vegetables from the Alliaceae family.

Saturated fat ingestion stimulates proatherogenic inflammation in polycystic ovary syndrome.

Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with ISOGTT and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation.NEW & NOTEWORTHY This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.

Over-Expression of Intestinal Alkaline Phosphatase Attenuates Atherosclerosis.

[Figure: see text].

Helicobacter pylori Infection Acts Synergistically with a High-Fat Diet in the Development of a Proinflammatory and Potentially Proatherogenic Endothelial Cell Environment in an Experimental Model.

Classic atherosclerosis risk factors do not explain all cases of chronic heart disease. There is significant evidence that gut microbiota may influence the development of atherosclerosis. The widespread prevalence of chronic Helicobacter pylori (H. pylori, HP) infections suggests that HP can be the source of components that stimulate local and systemic inflammatory responses. Elevated production of reactive oxygen species during HP infection leads to cholesterol oxidation, which drives atherogenesis. The aim of this study is to explore the link between persistent HP infection and a high-fat diet in the development of proinflammatory conditions that are potentially proatherogenic. An in vivo model of Caviae porcellus infected with HP and exposed to an experimental diet was investigated for the occurrence of a proinflammatory and proatherogenic endothelial environment. Vascular endothelial primary cells exposed to HP components were tested in vitro for oxidative stress, cell activation and apoptosis. The infiltration of inflammatory cells into the vascular endothelium of animals infected with HP and exposed to a high-fat diet was observed in conjunction with an increased level of inflammatory markers systemically. The arteries of such animals were the least elastic, suggesting the role of HP in arterial stiffness. Soluble HP components induced transformation of macrophages to foam cells in vitro and influenced the endothelial life span, which was correlated with Collagen I upregulation. These preliminary results support the hypothesis that HP antigens act synergistically with a high-fat diet in the development of proatherogenic conditions.

Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross.

Mice have provided critical mechanistic understandings of clinical traits underlying metabolic syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content, which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.

Pulmonary and vascular effects of acute ozone exposure in diabetic rats fed an atherogenic diet.

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.