Changes In Plasma Cholesterol Research Articles

Changes in soluble LDL receptor and lipoprotein fractions in response to diet in the DIETFITS weight loss study

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.

Conditional deletion of Ccl2 in smooth muscle cells does not reduce early atherosclerosis in mice

Background and aimsC–C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout of Ccl2 reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice. MethodsSMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtype Ccl2 alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and a high-fat diet for 12 weeks. ResultsUnexpectedly, mice with SMC-specific Ccl2 deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes. ConclusionsSMC-specific deficiency of Ccl2 does not significantly affect early plaque development in hypercholesterolemic mice.

Thioredoxin1 Gene Modulates Bcl2/p53/NF-KB Signaling Pathways in Strawberry Extract/Paracetamol-treated Rat Model of Acute Liver Injury

When used in excess, the analgesic paracetamol can cause hepatic centrilobular necrosis, which can be fatal. The goal of this study was to see if strawberry extract could protect rats' livers from paracetamol-induced hepatotoxicity. Strawberry (75 and 150 mg/kg bw) and vit C (1 g /kg bw) were given orally, daily for 15 days demonstrated a significant reduction in the effects of caused changes in plasma cholesterol, triacylglycerol, phospholipids and vit C, TBARS, GSH, TNF-α, IL-4 and NO, AST, ALT, ALP, LDH, SOD, GPx and GSH levels. Furthermore, strawberry extract significantly inhibits hepatocyte B-cell lymphoma 2 (Bcl2) but significantly induces p53, NF-KB and Trx1 gene expression compared to paracetamol- treated rats. Histological examination showed that significant normalization has been observed in strawberry extract treated rats. Conclusions Strawberry extract shows considerable hepatoprotective benefits in the case of paracetamol-induced liver damage, confirming it's essential use as a treatment for liver damage.

Role of intestinal tryptophan metabolism in atherosclerosis

The obesogenic diet (HFD) is responsible for intestinal dysbiosis observed especially in obesity. Indoleamine 2,3-dioxygenase 1 (IDO) is the main enzyme responsible for the degradation of Tryptophan (Trp), an essential amino acid, in extra-hepatic organs. Our team has shown that the total invalidation of IDO in the presence of HFD contributes to the reduction of metabolic complications. However, the specific role of intestinal IDO locally in the gut as well as its systemic effects on the development of atherosclerosis are unknown. Study of the impact of HFD (High Fat Diet) and HC (High Cholesterol), in the context of a specific invalidation of IDO in intestinal epithelial cells (IEC) on intestinal homeostasis and atherosclerosis. Mice genetically deficient for IDO in IEC and for LDLr (low density lipoprotein receptor) were created. They were subjected to HFD + HC or HC diet for 8 or 13 weeks, to develop atherosclerosis. Feces were collected to characterize microbiota. The heart and the aorta were harvested to analyze the development of atheromatous plaques as well as the inflammatory infiltrate. The invalidation of IDO in IEC contributes to a significant decrease in its expression in the intestine, indicating the importance of IEC in the intestinal expression of IDO. This invalidation in HFD + HC condition but not HC condition contributes to a significant increase in the size of atherosclerotic plaques in the aortic sinus as well as lymphocyte accumulation within the plaques, without any significant changes in plasma cholesterol. It also contributes to dysbiosis as well as intestinal inflammation. The expression of IDO in IEC has a local protective role at the intestine and on the systemic development of atherosclerosis, in the HFD condition. We will continue this project by determining the impact of other pathways of intestinal tryptophan catabolism on atherosclerosis.

Abstract 153: The Differential Effects Of Weight Loss And Regain On Atherosclerosis

Heightened inflammation in obesity is a major contributor to many diseases, including atherosclerosis and other cardiovascular diseases (CVD). Although weight loss is extremely beneficial in improving many obesity-related conditions, weight regain worsens disease outcomes, including CVD, compared to maintenance of an obese state. Nonetheless, how weight loss promotes inflammation resolution and why weight regain worsens inflammation is poorly understood and was investigated here. Using high-fat high-cholesterol diet feeding of atherogenic mice (Ldlr deficient), we promoted weight loss after the establishment of atherosclerosis and obesity by using dietary restriction, e.g. reducing daily food consumption by 30% for 2 weeks, while maintaining hyperlipidemia. For weight regain, some mice were then given free access to food for 6 weeks. Strikingly, after 2 weeks of dietary restriction we observed atherosclerosis resolution, while weight regain accelerated disease re-progression. Single-cell analysis of visceral adipose and plaque leukocytes revealed enrichment in both tissues of a novel macrophage population with dietary restriction, which is distinguished by high expression of the antibody receptor Fcgr4, a known phagocytosis mediator. Conversely, Fcgr4 + macrophages disappeared from plaques and adipose following weight regain. Mechanistically, Fcgr4 + macrophages from the adipose tissue induced clearance of plaque necrotic core via enhanced efferocytosis. Moreover, we discovered that weight loss and regain differentially influence immune progenitors. Bone marrow (BM) transplantation showed that while weight loss and obese BM recipients had similar plaque inflammation, weight regain BM recipients had larger, more inflammatory plaques. In conclusion, our data are the first to directly show that initial weight loss promotes resolution of atherosclerosis, independently of plasma cholesterol changes and through the enrichment of specialized pro-resolving macrophages in adipose tissue that communicate with plaques. Conversely, weight regain accelerates disease progression via inflammatory reprogramming of immune progenitors.

Differences in response to egg-derived dietary cholesterol result in distinct lipoprotein profiles while plasma concentrations of carotenoids and choline are not affected in a young healthy population

Abstract Background It has been demonstrated that some individuals (approximately 1/3 of the population) can be classified as hyper-responders to dietary cholesterol. Objective The objective of this study was to evaluate whether the response to dietary cholesterol (provided by eggs) would mediate lipoprotein metabolism and the bioavailability of lutein, zeaxanthin, and choline, nutritional components present in eggs. Methods We recruited 36 healthy subjects who underwent a two-week washout period in which they consumed zero eggs. Participants were then consecutively fed 1, 2, and 3 eggs/day for 4 weeks each. In this analysis, we compared intake of 0 eggs/day to 3 eggs/day (540 additional mg of dietary cholesterol/day). Plasma lipids, lipoprotein particle subfractions, and plasma lutein, zeaxanthin, and choline were measured. We classified the normal plasma response to dietary cholesterol as an increase of 2.2 mg/dL for each 100 mg of dietary cholesterol/day. Therefore, those individuals with >12 mg/dL increase in plasma cholesterol after the intervention (n = 12) were considered hyper-responders while the remaining 24 subjects presented changes in plasma cholesterol ranging from −16 to 9 mg/dL and were considered normal responders. Results Compared to 0 eggs, hyper-responders had significant increases in plasma total, LDL and HDL cholesterol (p Conclusions These results suggest that egg intake increases the bioavailability of carotenoids and choline present in eggs independently of individual responses to dietary cholesterol. Further, the observed increases in large HDL in all individuals could be associated with HDL being a major transporter of lutein and zeaxanthin in plasma.

Differences in Response to Egg Intake Result in Distinct Lipoprotein Profiles While Plasma Concentrations of Carotenoids and Choline Are Not Affected (P08-102-19)

ObjectivesIt has been demonstrated that some individuals (approximately 1/3 of the population) can be classified as hyper-responders to dietary cholesterol. The objective of this study was to evaluate whether the response to dietary cholesterol (provided by eggs) would affect lipoprotein metabolism and the bioavailability of lutein, zeaxanthin and choline, nutritional components present in eggs. MethodsWe recruited 36 healthy subjects who underwent a two-week washout period in which they consumed zero eggs. Participants were then fed 3 eggs (540 additional mg of dietary cholesterol) for 4 weeks. Plasma lipids were measured by use of an automated chemical clinical analyzer; the number of large and small LDL and HDL particles were measured by Nuclear Magnetic Resonance. Plasma lutein and zeaxanthin were determined by use of HPLC and plasma choline by use of LSM spectroscopy. We classified the normal response to dietary cholesterol as 2.2 mg/dL for each additional 100 mg of dietary cholesterol. Therefore, those individuals who had >12 mg/dL increase in plasma cholesterol after the intervention (n = 12) were considered hyper-responders while the other 24 subjects who presented changes in plasma cholesterol ranging from −16 to 9 mg/dL were considered hypo-responders. ResultsCompared to zero eggs, hyper-responders had significant increases in plasma total, LDL and HDL cholesterol (P < 0.001) with no changes in the LDL/HDL ratio. They also had higher concentrations of large LDL (P < 0.01) with no changes in small LDL. In contrast no changes in plasma total LDL or HDL cholesterol or large LDL were observed in hypo-responders after the consumption of 3 eggs/day. Interestingly, both hypo and hyper-responders had significant increases in large HDL particles (12%), plasma lutein (17%), zeaxanthin (30%) and choline (12%) (P < 0.001) compared to zero egg intake. ConclusionsThese results suggest that egg intake increases the bioavailability of carotenoids and choline present in eggs independently of plasma cholesterol response to dietary cholesterol. Further, the observed increases in large HDL in all individuals could be associated with HDL being a major transporter of lutein and zeaxanthin in plasma. Funding SourcesThe Esperance Family and the Egg Nutrition Center.

Low cholesterol is not always good: low cholesterol levels are associated with decreased serotonin and increased aggression in fish.

ABSTRACTThe inverse relationship between serum cholesterol and levels of aggression led to the cholesterol-serotonin hypothesis. According to this hypothesis, low dietary cholesterol intake leads to depressed central serotonergic activity, which is associated with increased aggression. Here we present the hypothesis about the evolutionary origins of low cholesterol and aggressive behavior, investigating the relationship between low levels of plasma cholesterol and aggressive behavior in fish. We used Nile tilapia (Oreochromis niloticus), a species of aggressive fish with a clear dominant subordinate relation, as an experimental model. The fish were treated with statin, a cholesterol-lowering drug. Aggressive behavior, brain serotonin (5-HT) concentrations, 5-hydroxyindoleacetic acid (5-HIAA, the major 5-HT metabolite) and plasma cholesterol were analyzed after chronic administration of statin. Our results show that fish treated with statin exhibited reduced plasma cholesterol, reduced telencephalic indexes of 5-HIAA/5-HT and increased aggressive behavior compared to control fish. These results indicate that changes in plasma cholesterol may affect neurochemical processes underlying aggressive behavior in fish, suggesting an evolutionary mechanism conserved among vertebrates. Such mechanisms may be important for the control of aggression in many vertebrate species, not just mammals, as has been demonstrated so far.

Sesame Oil and an Aqueous Extract Derived from Sesame Oil Enhance Regression of Preexisting Atherosclerotic Lesions in Low-Density Lipoprotein Receptor Knockout Mice.

Diet and exercise are recommended both as a prophylactic and as a therapeutic approach for patients with established coronary artery disease. We previously reported that sesame oil (SESO) and its aqueous extract (SOAE) showed antiatherosclerotic and anti-inflammatory properties. We also observed that genes involved in reverse cholesterol transport (RCT) might be activated. In this study, we tested whether post-treatment with SESO or SOAE would reduce preexisting atherosclerosis by enhancing RCT. Female low-density lipoprotein receptor knockout (LDL-R-/-) mice were fed an atherogenic diet for 3 months, followed by post-treatment with either control or SESO or SOAE for 1 month. Plasma lipids and atherosclerotic lesions were quantified at the end of the study. RNA was extracted from the aortic tissues and used for real-time polymerase chain reaction analysis. SESO and SOAE post-treatment significantly reduced atherosclerotic lesions in LDL-R-/- mice compared to controls. No significant change in plasma cholesterol, triglyceride, or LDL cholesterol levels was observed. Aortic gene analysis showed that the SESO/SOAE post-treatment reduced inflammatory gene expression and induced genes involved in cholesterol metabolism and RCT. This is the first study that demonstrates that post-treatment with SESO and SOAE could be an effective treatment for preexisting atherosclerosis and inflammation. The study also may suggest that reducing inflammation might be conducive to an accelerated regression of lesions.

Diploid and triploid African catfish (Clarias gariepinus) differ in biomarker responses to the pesticide chlorpyrifos

The impacts of environmental stressors on polyploid organisms are largely unknown. This study investigated changes in morphometric, molecular, and biochemical parameters in full-sibling diploid and triploid African catfish (Clarias gariepinus) in response to chlorpyrifos (CPF) exposures. Juvenile fish were exposed to three concentrations of CPF (mean measured μg/L (SD): 9.71 (2.27), 15.7 (3.69), 31.21 (5.04)) under a static-renewal condition for 21days. Diploid control groups had higher hepatosomatic index (HSI), plasma testosterone (T), and brain GnRH and cyp19a2 expression levels than triploids. In CPF-exposed groups, changes in HSI, total weight and length were different between the diploid and triploid fish. In contrast, condition factor did not alter in any of the treatments, while visceral-somatic index (VSI) changed only in diploids. In diploid fish, exposure to CPF did not change brain 11β-hsd2, ftz-f1, foxl2, GnRH or cyp19a2 mRNA levels, while reduced tph2 transcript levels compared to the control group. In contrast, 11β-hsd2 and foxl2 expression levels were changed in triploids following CPF exposures. In diploids, plasma T levels showed a linear dose-response reduction across CPF treatments correlating with liver weight and plasma total cholesterol concentrations. In contrast, no changes in plasma cholesterol and T concentrations were observed in triploids. Plasma cortisol and 17-β estradiol (E2) showed no response to CPF exposure in either ploidy. Results of this first comparison of biomarker responses to pesticide exposure in diploid and polyploid animals showed substantial differences between diploid and triploid C. gariepinus.

Relative VO2 max correlates with lipoprotein subfractions in response to four different exercise modalities

Exercise variably increases high density lipoprotein, HDL, cholesterol; little information is available for effects on density distributions that may better reflect HDL functionality. 45 normolipidemic, untrained subjects completed one of four exercise modalities that progressively increased energy expenditure over a 8wk period without diet change. From wk 8‐12 exercise intensity was constant and created a 500 kcal/wk expenditure for each modality. Density distributions were determined by imaging fluorescently stained plasma lipoproteins follow isopycnic separation before and at the end of the 12 wk training period. Body fat was determined by DEXA and averaged 40.2% at week 0 and 38.4% at week 12 (p&lt;0.05); relative VO2 max mL O2/min/kg body weight increased 13% from 30.0 to 33.9 over this same time interval (p &lt; 0.05). Total lipoprotein area under the curve did not change with exercise. No lipoprotein subfraction was found to be associated with relative VO2 max in untrained individuals. At week 12, regardless of exercise group, relative VO2 max was negatively correlated (p&lt;0.05) with HDL3b, low‐density lipoprotein subfraction 2, LDL2, and LDL3. These findings show that increasing VO2 max, independent of exercise modality and diet modification, can have positive impact on lipoprotein profiles in the absence of changes in plasma cholesterol or HDL‐C.

Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation

BackgroundRecent studies have demonstrated a relationship between fructose consumption and risk of developing metabolic syndrome. Mechanisms by which dietary fructose mediates metabolic changes are poorly understood. This study compared the effects of fructose, glucose and sucrose consumption on post-postprandial lipemia and low grade inflammation measured as hs-CRP.MethodsThis was a randomized, single blinded, cross-over trial involving healthy subjects (n = 14). After an overnight fast, participants were given one of 3 different isocaloric drinks, containing 50 g of either fructose or glucose or sucrose dissolved in water. Blood samples were collected at baseline, 30, 60 and 120 minutes post intervention for the analysis of blood lipids, glucose, insulin and high sensitivity C-reactive protein (hs-CRP).ResultsGlucose and sucrose supplementation initially resulted in a significant increase in glucose and insulin levels compared to fructose supplementation and returned to near baseline values within 2 hours. Change in plasma cholesterol, LDL and HDL-cholesterol (measured as area under curve, AUC) was significantly higher when participants consumed fructose compared with glucose or sucrose (P < 0.05). AUC for plasma triglyceride levels however remained unchanged regardless of the dietary intervention. Change in AUC for hs-CRP was also significantly higher in subjects consuming fructose compared with those consuming glucose (P < 0.05), but not sucrose (P = 0.07).ConclusionThis study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. The significance of increase in HDL-cholesterol with a concurrent increase in LDL-cholesterol and elevated hs-CRP levels remains to be delineated when considering health effects of feeding fructose-rich diets.Registration number for clinical trialsACTRN12614000431628

Age effects on plasma cholesterol and triglyceride profiles and metabolite concentrations in dogs

BackgroundIn dogs, occurrence of lipid metabolism disorders such as obesity and diabetes mellitus has increased markedly in recent years. Hyperlipidemia has been regarded as a common characteristic for obese animals and hyperlipidemic condition may be associated with inflammation, oxidative stress and lipid composition changes. In this study, we investigated the changes in plasma cholesterol and triglyceride (TG) profiles and metabolite concentrations in 24 dogs (young group: 0-7 years old, n = 12, aged group: 8-13 years old, n = 12).ResultsPlasma adiponectin (ADN) concentrations were significantly lower in aged dogs than those in young dogs (mean ± SD, 17.2 ± 10.0 μg mL-1 vs 29.3 ± 12.5 μg mL-1, respectively; P <0.05). Although there were no significant differences statistically, aged dogs showed significantly higher plasma alpha1- acid glycoprotein (alpah1-AG) levels compared to those in young dogs. Plasma cholesterol lipoprotein and TG lipoprotein were divided into four fractions by biphasic agarose gel electrophoresis technique. The levels of the third TG-lipoprotein fraction from the positive pole (TG Fraction 3) were significantly higher in aged dogs than in young dogs (mean ± SD, 143.0 ± 109.3 mg dL-1 vs 55.2 ± 31.3 mg dL-1, respectively; P <0.05). On the correlation coefficient analysis by Peason’s method, moderate positive correlations were seen between the age and TG (r = 0.446, P = 0.029), TG Fraction 3 (r = 0.516, P = 0.010), malondialdehyde (r = 0.146, P = 0.043), alpha-1 AG (r = 0.448, P = 0.028) levels, respectively. Moderate negative correlations were seen the age and total cholesterol (TC) Fraction 2 (r = -0.446, P = 0.029), glucose (r = -0.637, P = 0.001), ADN (r = -0.408, P = 0.048), respectively.ConclusionsPresent data suggest biochemical characteristics of lipid metabolism disorder may be affected by aging in dogs.

An Immunomodulating Fatty Acid Analogue Targeting Mitochondria Exerts Anti-Atherosclerotic Effect beyond Plasma Cholesterol-Lowering Activity in apoE-/- Mice

Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs) and proliferation of mitochondria. This study aimed to penetrate the effect of TTA on the development of atherosclerotic lesions in apolipoprotein (apo)-E-/- mice fed a high-fat diet containing 0.3% TTA for 12 weeks. These mice displayed a significantly less atherosclerotic development vs control. Plasma cholesterol was increased by TTA administration and triacylglycerol (TAG) levels in plasma and liver were decreased by TTA supplementation, the latter, probably due to increased mitochondrial fatty acid oxidation and reduced lipogenesis. TTA administration also changed the fatty acid composition in the heart, and the amount of arachidonic acid (ARA) and eicosapentaenoic acid (EPA) was reduced and increased, respectively. The heart mRNA expression of inducible nitric oxidase (NOS)-2 was decreased in TTA-treated mice, whereas the mRNA level of catalase was increased. Finally, reduced plasma levels of inflammatory mediators as IL-1α, IL-6, IL-17, TNF-α and IFN-γ were detected in TTA-treated mice. These data show that TTA reduces atherosclerosis in apoE-/- mice and modulates risk factors related to atherosclerotic disorders. TTA probably acts at both systemic and vascular levels in a manner independent of changes in plasma cholesterol, and triggers TAG catabolism through improved mitochondrial function.

Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: A critical role for heme oxygenase-1

Several lines of evidence indicate that quercetin, a polyphenol derived in the diet from fruit and vegetables, contributes to cardiovascular health. We aimed to investigate the effects of dietary quercetin on endothelial function and atherosclerosis in mice fed a high-fat diet. Wild-type C57BL/6 (WT) and apolipoprotein E gene knockout (ApoE−/−) mice were fed: (i) a high-fat diet (HFD) or (ii) a HFD supplemented with 0.05% w/w quercetin (HFD+Q), for 14 weeks. Compared with animals fed HFD, HFD+Q attenuated atherosclerosis in ApoE−/− mice. Treatment with the HFD+Q significantly improved endothelium-dependent relaxation of aortic rings isolated from WT but not ApoE−/− mice and attenuated hypochlorous acid-induced endothelial dysfunction in aortic rings of both WT and ApoE−/− mice. Mechanistic studies revealed that HFD+Q significantly improved plasma F2-isoprostanes, 24h urinary nitrite, and endothelial nitric oxide synthase activity, and increased heme oxygenase-1 (HO-1) protein expression in the aortas of both WT and ApoE−/− mice (P<0.05). HFD+Q also resulted in small changes in plasma cholesterol (P<0.05 in WT) and plasma triacylglycerols (P<0.05 in ApoE −/−mice). In a separate experiment, quercetin did not protect against hypochlorite-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 gene knockout mice with low expression of HO-1 protein. Quercetin protects mice fed a HFD against oxidant-induced endothelial dysfunction and ApoE−/− mice against atherosclerosis. These effects are associated with improvements in nitric oxide bioavailability and are critically related to arterial induction of HO-1.

Complement monitoring of Pluronic 127 gel and micelles: Suppression of copolymer-mediated complement activation by elevated serum levels of HDL, LDL, and apolipoproteins AI and B-100

Poloxamer 407 is a non-ionic polyethylene oxide (PEO)/polypropylene oxide (PPO) block copolymer, which exhibits reversible thermogelation properties. Poloxamer gel has attracted many applications for controlled release of therapeutic agents as well as in surgical interventions such as controlled vascular occlusion. We show that poloxamer gel can trigger the complement system, which is an integral part of innate immunity and its inadvertent activation can induce clinically significant anaphylaxis. Complement activation by the poloxamer gel is through the alternative pathway, but material transformations from gel to the solution state further incite complement through calcium-sensitive pathways, where a role for C1q and antibodies has been eliminated. Poloxamer addition to plasma/serum (at levels above its critical micelle concentration, cmc) induced formation of large and diffused structures, which may have been responsible for triggering complement. Since poloxamer 407 administration has been reported to cause significant changes in plasma cholesterol and triglyceride levels we further examined the role of lipoproteins in poloxamer-mediated complement activation. Our results show a protective role for elevated serum HDL, LDL and their predominant apolipoproteins (apoAI and apoB-100, respectively) on poloxamer-mediated complement activation. Electron microscopy investigations indicated formation of two distinct populations of new structures on mixing of poloxamer (at concentrations above its cmc) with human LDL, which could have played a significant role in regulating complement activation. These observations are in line with the suggested modulatory role of lipoproteins in host defence and inflammatory processes. A better understanding of block copolymer interaction with lipoproteins/apolipoproteins could improve the immune safety of surgical and therapeutic interventions requiring PEO/PPO block copolymers and may provide new insights for combinatorial design of multifunctional copolymers.

Changes in the metagenome and plasma lipids of hamsters fed high fat diets containing Chardonnay grape seed flour

The relationship between changes in the metagenome and cholesterol lowering by defatted chardonnay grape seed were evaluated in male Syrian hamsters fed high‐fat (HF) diets. The diets were supplemented with 10% grape seed flours from chardonnay (CH) or cabernet sauvignon (CS) grapes and compared to a HF diet containing microcrystalline cellulose dietary fiber (control) for three weeks. Hamsters fed the CH diet had significantly lowered plasma total‐, VLDL‐, and LDL‐cholesterol concentrations compared to the control and CS diets. These improved plasma cholesterol changes were correlated with the upregulation of hepatic genes related to cholesterol and bile acid synthesis (CYP51, CYP7A1, and LDLR). Fecal total bacteria concentration was decreased by the CH diet but not significantly (P = 0.056). The CH diet significantly lowered fecal bifidobacterium spp. and lactobacillus spp. concentration compared to control and CS diets. The fecal lactobacillus spp. concentrations from control, CH, and CS groups were significantly positively correlated with plasma total‐ (r=61.6) and LDL‐ cholesterol (r=69.3) concentrations, indicating cholesterol lowering by chardonnary grape seed flour were not due to fecal lactobacillus spp. concentration. Antimicrobial activity of grape seed flour on the intestinal microbiota warrants further investigation.

The 10 Most Read Articles Published in Circulation Research in 2012

The 10 Most Read Articles Published in <i>Circulation Research</i> in 2012

Nitric Oxide-Donating Atorvastatin Attenuates Neutrophil Recruitment During Vascular Inflammation Independent of Changes in Plasma Cholesterol

Polymorphonuclear neutrophils, the first leukocytes to infiltrate the inflamed tissue, can make important contributions to vascular inflammatory processes driving the development of atherosclerosis. We herein investigated the effects of atorvastatin and NCX 6560 (a nitric oxide (NO)-donating atorvastatin derivative that has completed a successful phase 1b study) on neutrophilic inflammation in carotid arteries of normocholesterolemic rabbits subjected to perivascular collar placement. Atorvastatin or NCX 6560 were administered orally (5 mg/kg/day or equimolar dose) to New Zealand White rabbits for 6 days, followed by collar implantation 1 h after the last dose. Twenty-four hours later carotids were harvested for neutrophil quantification by immunostaining. Treatment with NCX 6560 was associated with a lower neutrophil infiltration (-39.5 %), while atorvastatin did not affect neutrophil content. The result was independent of effects on plasma cholesterol or differences in atorvastatin bioavailability, which suggests an important role of NO-related mechanisms in mediating this effect. Consistent with these in vivo findings, in vitro studies showed that NCX 6560, as compared to atorvastatin, had greater inhibitory activity on processes involved in neutrophil recruitment, such as migration in response to IL-8 and IL-8 release by endothelial cells and by neutrophils themselves. Pretreatment with NCX 6560, but not with atorvastatin, reduced the ability of neutrophil supernatants to promote monocyte chemotaxis, a well-known pro-inflammatory activity of neutrophils. Experimental data suggest a potential role of NO-releasing statins in the control of the vascular inflammatory process mediated by polymorphonuclear neutrophils.

11β-Hydroxysteroid Dehydrogenase Type 1 Gene Knockout Attenuates Atherosclerosis and In Vivo Foam Cell Formation in Hyperlipidemic apoE−/− Mice

BackgroundChronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11βHSD1 has been shown to reduce atherosclerosis in murine models. However, the cellular and molecular details for this effect have not been elucidated.Methodology/Principal FindingsTo examine the role of 11βHSD1 in atherogenesis, 11βHSD1 knockout mice were created on the pro-atherogenic apoE−/− background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50% in 11βHSD1−/−/apoE−/− mice vs. 11βHSD1+/+/apoE−/− mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40% in 11βHSD1−/−/apoE−/− mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced ∼30% in 11βHSD1−/−/apoE−/− mice. Bone marrow transplantation from 11βHSD1−/−/apoE−/− mice into apoE−/− recipients reduced plaque area 39–46% in the thoracic aorta. In vivo foam cell formation was evaluated in thioglycollate-elicited peritoneal macrophages from 11βHSD1+/+/apoE−/− and 11βHSD1−/−/apoE−/− mice fed a Western diet for ∼5 weeks. Foam cell cholesterol levels were reduced 48% in 11βHSD1−/−/apoE−/− mice vs. control. Microarray profiling of peritoneal macrophages revealed differential expression of genes involved in inflammation, stress response and energy metabolism. Several toll-like receptors (TLRs) were downregulated in 11βHSD1−/−/apoE−/− mice including TLR 1, 3 and 4. Cytokine release from 11βHSD1−/−/apoE−/−-derived peritoneal foam cells was attenuated following challenge with oxidized LDL.ConclusionsThese findings suggest that 11βHSD1 inhibition may have the potential to limit plaque development at the vessel wall and regulate foam cell formation independent of changes in plasma lipids. The diminished cytokine response to oxidized LDL stimulation is consistent with the reduction in TLR expression and suggests involvement of 11βHSD1 in modulating binding of pro-atherogenic TLR ligands.