Arterial Cholesterol Research Articles

Resveratrol as a supplement to exercise training: friend or foe?

Resveratrol as a supplement to exercise training: friend or foe?

Macrophages, extracellular matrix, and lipoproteins in arterial cholesterol balance

Freeman and collaborators (1) report in the current issue of the Journal of Lipid Research important findings indicating that cholesterol-loaded macrophages secrete unesterified cholesterol (UC) complexes that are deposited as microdomains within the cell surface of the macrophages, as well as in their secreted extracellular matrix (ECM). Furthermore, the experiments indicate that these microdomains participate in the initial steps of the reverse-cholesterol pathways (1). The UC-microdomains are rich in cholesterol monohydrate aggregates that are recognized by MAb 58B1, an antibody generated against cholesterol crystals and that specifically recognizes ordered arrays with a minimum of 12 cholesterol monohydrate molecules (2). Deposition of the ECM and cell surface UC-cholesterol microdomains required overloading of macrophages with cholesterol as well as functional ABCA1 and ABCG1 transporters (3). Importantly, Freeman et al. show that the deposition of cholesterol-rich microdomains in the macrophage's surface and in the ECM as a consequence of acetylated (Ac)-LDL loading could be inhibited by the presence of 50 μg/ml apoAI in the incubation. However, when intact HDL was used at a similar concentration, it did not inhibit deposition of the UC-microdomains in the cell surface, although this did occur when HDL was used at a concentration of 200 μg/ml.

Changes in Renal Glucose Transporters in an Animal Model of Metabolic Syndrome

Considering the similarity between structural, hemodynamic, and functional changes of obesity-related renal disease and diabetic nephropathy, we hypothesized that renal glucose transporter changes occur in obesity as in diabetes. The aim of the work was to evaluate GLUT1 and GLUT2 in kidneys of an animal model of metabolic syndrome. Neonate spontaneously hypertensive rats (SHR), n=15/group, were treated with monosodium glutamate (5 mg/g) (MetS) for 9 days and compared with saline-treated Wistar-Kyoto (C) and SHR (H) rats. Lee index, systolic arterial pressure (SAP), glycemia, insulin resistance, triglycerides, and HDL cholesterol were evaluated at 3 and 6 months. Medullar GLUT1 and cortical GLUT2 were analyzed by Western blot. MetS vs. C and H rats had the highest Lee index (p<0.001) and insulin resistance (3-months C: 4.3±0.7, H: 3.9±0.9, MetS: 2.7±0.6; 6-months C: 4.2±0.6, H: 3.8±0.5, MetS: 2.4±0.6% · min⁻¹, p<0.001), similar glycemia, and the lowest HDL-cholesterol at 6-months (p<0.001). In the MetS and H rats, SAP was higher vs. C at 3-months (p<0.001) and 6-months (C: 151±15, H: 190±11, MetS: 185±13 mm Hg, p<0.001) of age. GLUT1 was ̴ 13× lower (p<0.001) at 3-months, reestablishing its content at 6-months in MetS group, while GLUT2 was 2× higher (p<0.001) in this group at 6-months of age. Renal GLUT1 and GLUT2 are modulated in kidney of rats with metabolic syndrome, where obesity, insulin resistance and hypertension coexist, despite normoglycemia. Like in diabetes, cortical GLUT2 overexpression may contribute to the development of kidney disease.

Prevalence of Metabolic Syndrome Risk Factors in High School and NCAA Division I Football Players

Metabolic syndrome (MetSyn) is a clustering of metabolic and cardiovascular disease risk factors. The purpose of this study was to determine the prevalence of MetSyn risk factors in high school (HS) and college (College) football players and to examine if the prevalence varied according to body fat percent (%Fat). One hundred twenty-three males (height 179.0 ± 6.7 cm; weight 89.4 ± 19.6 kg) from 7 different high schools and 82 males (height 186.2 ± 6.8 cm; weight 99.6 ± 16.8 kg) from one university participated. All testing occurred in the early morning after an overnight fast. %Fat, waist circumference, resting systolic and diastolic blood pressure, fasting triglyceride, high-density lipoprotein (HDL) cholesterol, and blood glucose were determined using standard testing procedures. The MetSyn risk factor levels were determined using American Heart Association criteria. Subjects were grouped by position and playing level (HS, College). Independent t-tests, chi-square analysis, 2-way analysis of variance, and path analytic models were used in the statistical analysis. Significance was set at p < 0.05. 6.8% (n = 14) of the sample met the American Heart Association criteria for MetSyn. Offensive and defensive linemen accounted for 92.3% of the players meeting MetSyn criteria with each playing level (HS, College) having 7 subjects. The MetSyn criteria differed significantly across %Fat. Obese players were more likely to meet the criteria for MetSyn. %Fat was a statistically significant predictor of mean arterial blood pressure, HDL cholesterol, and waist circumference. The MetSyn exists in both HS- and College-level football players, with almost all cases occurring in the athletes with the highest levels of %Fat (offensive/defensive lineman). Strength and conditioning coaches should be aware of the prevalence of MetSyn risk factors in offensive and defensive linemen and take appropriate actions to ensure athlete safety.

Emerging role of lymphatic vessels in reverse cholesterol transport

As a major constituent of cell membrane, cholesterol is essential for cellular homeostasis through the control of membrane fluidity and permeability. Abnormal levels of cholesterol can have important cellular consequences and may lead to diseases such as atherosclerosis and type II diabetes. Therefore, cells have developed complex mechanisms to regulate the abundance of intracellular cholesterol. Among these mechanisms, the process referred to as reverse cholesterol transport (RCT) has been shown to be critical for the removal of excess cholesterol from peripheral tissues and its transport to the liver via plasma for excretion [1]. RCT is initiated when cells including macrophages efflux out the excess of cholesterol to prevent intracellular over-accumulation. This step is tightly regulated through the action of ATP-binding cassette transporters ABCA1, ABCG1 and scavenger receptor class BI (SR-BI) and high density lipoprotein (HDL) which serves as the major acceptor for cellular cholesterol released in extrahepatic tissues [2]. Following cholesterol efflux, HDL-cholesterol is transported from the tissue back into the blood circulation. In the final step of RCT, the majority of HDL-derived cholesterol is removed from the liver by secretion into the bile [1, 2]. In contrast to the knowledge on the mechanisms by which cholesterol is effluxed out of the cells and its fate after reaching the liver, little information is available on how HDL-cholesterol travels from the peripheral tissues back to the blood circulation. Since one of the major roles of lymphatic vessels is to drain macromolecules from the interstitial space back to the circulation and lymph is rich in cholesterol and HDL [3], the implication of lymphatics in the transport of lipoproteins from interstitium to blood has been suspected. The recent studies by Martel et al., and Lim et al., now provide convincing evidence for a role of lymphatic vessels in RCT [4, 5]. Indeed, impairment of lymphatic drainage induced by surgical excision in wild-type mice [4, 5] or naturally occurring in mice lacking the expression of one allele of vascular endothelial growth factor-C receptor [4] significantly decreased the efficiency of RCT. Furthermore, Lim et al., showed that the transport of effluxed cholesterol from peripheral tissue to the blood circulation via lymphatics is not passive as anticipated but an active process dependent on HDL and SR-BI [5]. Therefore, these new findings establish that lymphatic vessels tightly regulate RCT through the active transport of HDL-cholesterol. Accumulation of cholesterol in tissues including arteries and skin is a hallmark of atherosclerosis and xanthomas, respectively, and these features are recapitulated in mouse models lacking apoE (apoE−/−) or LDL receptor which develop hypercholesterolemia. Interestingly, we showed previously that skin lymphatic vessels in these hypercholesterolemic mice exhibit structural defects which severely compromise their function [6]. These observations suggest that the accumulation of cholesterol in arteries and skin from hyper-cholesterolemic mice may result from poor lymphatic drainage. We now provide definitive evidence that restoring lymphatic function in apoE−/− mice ameliorates the clearance of cholesterol from skin by supporting RCT [5]. In strong agreement with these findings in skin, Martel et al., showed in an elegant surgical model of aorta transplantation that impeding lymphatic vessel growth interferes with the removal of cholesterol from the transplanted aorta [4]. Altogether, these findings reveal the potential atheroprotective role of lymphatic drainage by actively contributing to RCT. The relevance of these findings in humans is supported by clinical studies reporting a possible interconnection between lymphatic function and lipid accumulation in tissues (Figure ​(Figure1).1). Patients with familial combined hyperlipidemia, a genetic dyslipidemia, which share similar clinical and biochemical features with type II diabetes mellitus, obesity and the metabolic syndrome showed decreased expression of FOXC2 and Prox-1 genes in their adipose tissue [7]. Since these two genes regulate the structure and function of lymphatic vessels these findings support the hypothesis that defective lymphatic drainage may contribute to this lipid disorder. Massive lipid deposits are evident in the edematous tissues of patients with lymphedema and poor lymphatic drainage has been associated with the formation of xanthomas in humans [8]. However, it remains to be determined whether RCT is affected in patients with lymphedema. Interestingly, the use of compression garments to resolve lymphedema ameliorate xanthomatous eruptions in patients [8]. Therefore, promoting efficient lymphatic drainage in lipid-related diseases including atherosclerosis and diabetes whose prevalence will continue to augment as a result of increase in aging population may be an attractive therapeutic intervention that deserves future investigations. Figure 1 Lymphatic vessels are important for peripheral lipid clearance. Under normocholesterolemic conditions, functional lymphatic vessels regulate cholesterol transport from extra-hepatic tissues by contributing to RCT. Hypercholesterolemic conditions results ...

Variáveis bioquímicas, antropométricas e pressóricas como indicadores de risco cardiovascular em servidores públicos

INTRODUÇÃO: As doenças cardiovasculares têm sido apontadas como a principal causa de mortalidade e morbidade no Brasil e no mundo. OBJETIVO: Verificar a prevalência dos fatores de risco cardiovascular em servidores universitários, utilizando as variáveis bioquímicas, antropométricas e pressóricas. MATERIAIS E MÉTODOS: Participaram do estudo 107 servidores técnico-administrativos da Universidade Federal de Viçosa, no ano de 2010, com idade média de 46,1 ± 10,4 anos. Os parâmetros analisados foram: índice de massa corporal, relação cintura-quadril (RCQ), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD), colesterol total (CT), triglicerídeos (TG), lipoproteína de alta densidade (HDL-C) e lipoproteína de baixa densidade (LDL-C). A análise dos dados consistiu no cálculo das prevalências das variáveis estudadas. Para todos os tratamentos estatísticos adotou-se um nível de significância de p &lt; 0,05. RESULTADOS: Foram encontrados 45% de excesso de peso (IMC ≥ 25,0 kg/m²), 20% da população apresentou RCQ elevada (&gt; 0,85 para as mulheres e ≥ 0,95 para os homens), a pressão arterial se apresentou alta (PAS ≥ 140 mmHg; PAD ≥ 90mmHg) em 24% dos avaliados, o CT obteve 49% de valores elevados (&gt; 199 mg/dL), os triglicerídeos apresentaram 23% valores alterados (&gt; 149 mg/dL), em relação ao LDL-C foram encontrados 31% de valores acima de 129 mg/dL, e 30% dos avaliados apresentaram valores reduzidos de HDL-C (&lt; 40 mg/dL). Observamos que apenas 18,6% dos avaliados não apresentaram nenhum dos FRC analisados, sendo que cerca de metade dos servidores se encontraram na faixa de 2 a 4 FRC. CONCLUSÃO: Foi verificado um elevado percentual de FRC na população de servidores universitários. Dentre as variáveis analisadas, verificamos que excesso de peso, CT, níveis reduzidos de HDL-C e aumentados de LDL-C foram os FRC mais prevalentes.

Experimental Diet-Induced Atherosclerosis in Quaker Parrots (Myiopsitta monachus)

Spontaneous atherosclerosis is common in psittaciformes, and clinical signs associated with flow-limiting stenosis are encountered in pet birds. Nevertheless, a psittacine model of atherosclerosis has not been developed for research investigations. Sixteen captive-bred Quaker parrots (Myiopsitta monachus) were used in this study. While 4 control birds were fed a maintenance diet, 12 other birds were fed an atherogenic diet composed of 1% cholesterol controlling for a calorie-to-protein ratio for periods ranging from 2 to 8 months. The birds were euthanized at the end of their respective food trial period. Histopathology, transmission electron microscopy, and cholesterol measurement were performed on the ascending aorta and brachiocephalic and pulmonary arteries. Plasma lipoproteins, cholesterol, and triglycerides were also measured on a monthly basis. Significant atherosclerotic lesions were induced within 2 months and advanced atherosclerotic lesions within 4 to 6 months. The advanced lesions were histologically similar to naturally occurring lesions identified in the same parrot species with a lipid core and a fibrous cap. Ultrastructurally, there were extracellular lipid, foam cell, and endothelial changes. Arterial cholesterol content increased linearly over time. Plasma cholesterol and low-density lipoprotein (LDL) significantly increased over time by an average of 5- and 15-fold, respectively, with a shift from high-density lipoprotein to LDL as the main plasma lipoprotein. Quaker parrots also exhibited high plasma cholesteryl ester transfer protein activity that increased, although not significantly, over time. This experiment demonstrates that in Quaker parrots fed 1% cholesterol, advanced atherosclerosis can be induced relatively quickly, and lesions resemble those found in other avian models and humans.

Fluid-Phase Pinocytosis of Native Low Density Lipoprotein Promotes Murine M-CSF Differentiated Macrophage Foam Cell Formation

During atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates in macrophages to form foam cells. Macrophage uptake of LDL promotes foam cell formation but the mechanism mediating this process is not clear. The present study investigates the mechanism of LDL uptake for macrophage colony-stimulating factor (M-CSF)-differentiated murine bone marrow-derived macrophages. LDL receptor-null (LDLR−/−) macrophages incubated with LDL showed non-saturable accumulation of cholesterol that did not down-regulate for the 24 h examined. Incubation of LDLR−/− macrophages with increasing concentrations of 125I-LDL showed non-saturable macrophage LDL uptake. A 20-fold excess of unlabeled LDL had no effect on 125I-LDL uptake by wild-type macrophages and genetic deletion of the macrophage scavenger receptors CD36 and SRA did not affect 125I-LDL uptake, showing that LDL uptake occurred by fluid-phase pinocytosis independently of receptors. Cholesterol accumulation was inhibited approximately 50% in wild-type and LDLR−/− mice treated with LY294002 or wortmannin, inhibitors of all classes of phosphoinositide 3-kinases (PI3K). Time-lapse, phase-contrast microscopy showed that macropinocytosis, an important fluid-phase uptake pathway in macrophages, was blocked almost completely by PI3K inhibition with wortmannin. Pharmacological inhibition of the class I PI3K isoforms alpha, beta, gamma or delta did not affect macrophage LDL-derived cholesterol accumulation or macropinocytosis. Furthermore, macrophages from mice expressing kinase-dead class I PI3K beta, gamma or delta isoforms showed no decrease in cholesterol accumulation or macropinocytosis when compared with wild-type macrophages. Thus, non-class I PI3K isoforms mediated macropinocytosis in these macrophages. Further characterization of the components necessary for LDL uptake, cholesterol accumulation, and macropinocytosis identified dynamin, microtubules, actin, and vacuolar type H(+)-ATPase as contributing to uptake. However, Pak1, Rac1, and Src-family kinases, which mediate fluid-phase pinocytosis in certain other cell types, were unnecessary. In conclusion, our findings provide evidence that targeting those components mediating macrophage macropinocytosis with inhibitors may be an effective strategy to limit macrophage accumulation of LDL-derived cholesterol in arteries.

Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A‐I variant

Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano). ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild-type) mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. The dietary treatment led to a strong elevation in HDL-cholesterol levels in A-I(M) (ilano) mice, associated with an increased expression of hepatic ABCA1. ApoA-I(M) (ilano) mice showed lower cholesterol output from the liver compared with apoA-I(wild-type) mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-I(M) (ilano) mice, the net sterol excretion is comparable in the two transgenic lines.

ApoA-1 infusion reduces arterial cholesterol and myocardial lesions in a rat model of cardiac dysfunction and insulin resistance

ObjectiveLow plasma high-density lipoprotein cholesterol (HDL-C) concentration is associated with the metabolic syndrome (MetS) and increased prevalence of cardiovascular disease (CVD). Animal and human studies report infusion of apolipoprotein A-1 (apoA-1) can reduce endothelial dysfunction, and/or induce regression of atherosclerosis. However, the direct mechanisms underlying the vascular benefits of either apoA-1 or HDL-C remain unclear. In this study, we assessed the ability of reconstituted HDL (rHDL) to improve vascular complications of MetS, including left ventricular (LV)-hypertrophy, arterial cholesterol deposition and myocardial lesion development. Methods and resultsObese insulin resistant (IR) JCR:LA-cp rats were infused with rHDL (0.4mg/kg) over 3 days before assessing cardiac function (Echocardiography) at days 7 and 50 post-infusion, as well as haematoxylin and eosin staining of myocardial lesions at day 50. Acute ex vivo arterial cholesterol deposition was assessed with acute infusion of rHDL ex-vivo. Infusion of rHDL partially corrected abnormal diastolic compliance (18%; *p<0.05) and improved parameters of cardiac function in IR rats. Further, acute rHDL infusion in carotid vessels reduced remnant lipoprotein associated-cholesterol deposition (30–86%; **p<0.01) ex vivo in IR and male Wistar rats and reduced (41%; *p<0.05) the frequency of early-stage myocardial lesions in IR rats. ConclusionShort-term infusion of rHDL may beneficially reduce chronic vascular sequelae of MetS, including temporary improvement in LV-dysfunction, acute reduction of acute arterial cholesterol deposition and the development of early-stage myocardial lesions in the JCR:LA-cp rat.

Abstract MP085: Genotype Predicts Type 2 Diabetes in Adulthood in a Biracial Adolescent Population

Background Prediction of type 2 diabetes (T2D) early in the life course, before metabolic derangements occur, might facilitate prevention. In middle-aged adults, genotype risk scores (GRS) predict incident T2D but do not outperform prediction models consisting of clinical variables such as family history, body-mass index (BMI), and routine laboratory tests. Unlike clinical predictors and even family history, however, genotype does not change over the life course. We hypothesized that a diabetes GRS predicts incident adult T2D from adolescence and that the addition of this GRS improves T2D prediction models based on clinical adolescent risk factors alone. Methods The biracial Bogalusa Heart Study is a geographically based cohort study of children aged 4 to 18 years followed serially into adulthood. We limited the present analyses to participants seen in adolescence and followed into adulthood for whom genotype information was available. The baseline examination was the first assessment for each participant after age 12 years. Participants with childhood or type 1 diabetes were excluded. Incident T2D was defined as a fasting glucose ≥126 mg/dL or diabetes treatment after age 19 years. We used Cox regression to build nested T2D prediction models based on clinical risk factors assessed in adolescence (parental history of diabetes, BMI z -score, mean arterial pressure, fasting glucose, HDL cholesterol, and triglycerides) with and without a 38-variant GRS. We used likelihood ratios tests (LRT), differences in C statistics (ΔC), and net reclassification improvement indices (NRI) to assess whether GRS improved prediction in each model. Results Mean age at baseline was 14.4 years (range 12 to 19). Of the 1056 participants, 585 (55%) were girls, and 340 (32%) were black. Ninety (8.5%) developed T2D over a mean 26.3 years of follow-up. GRS significantly predicted incident T2D in all models, with hazard ratios of 1.09 per risk allele (95% CI 1.03, 1.15) in the basic demographic model and 1.06 (95% CI 1.00, 1.13) in the full model. The addition of GRS to all models improved model fit (all LRT p &lt;0.05) but not discrimination (all ΔC p &gt;0.05). The addition of GRS to the demographic model significantly improved the risk classification of the cohort (NRI 24.8%, 95% CI 8.3, 41.7%), but this reclassification was not significant when GRS was added to the full model (NRI 3.9%, 95% CI -5.0, 13.9%). Moreover, the GRS did not meaningfully improve prediction in a model which included only demographics and parental history of diabetes (NRI 0.8%, 95% CI -13.0, 16.0%). We found no interaction between race and GRS in any model (all p &gt;0.05). Conclusions Knowledge of genotype predicts adult T2D in white and black adolescents. Genotype does not meaningfully improve prediction over routinely collected clinical risk factors, including parental history.

Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels

Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels

Aortic valve involvement and premature coronary artery disease in Heterozygous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by an elevation of LDL cholesterol concentration in plasma leading to deposition of excess LDL-derived cholesterol in tendons, skin and arteries. We studied a 34 year old woman who applied to dermatology department due to multiple xanthomas. Cardiac consulting was demanded by dermatology department to determine development of atherosclerosis. Patient had no risk factor and symptom related to cardiac problem, except family history included premature coronary artery disease (CAD). On examination systolic murmur was present in aortic area. Echocardiography showed valvular severe aortic stenosis with a good left ventricle systolic function and severe left ventricular hypertrophy. The coronary arteriogram showed widespread CAD involving 3 coronary vessels. We report a case of heterozygous FH type II a with premature CAD and aortic valve involvement.

Activation of monocytes and cytokine production in patients with peripheral atherosclerosis obliterans

BackgroundArterial peripheral disease is a condition caused by the blocked blood flow resulting from arterial cholesterol deposits within the arms, legs and aorta. Studies have shown that macrophages in atherosclerotic plaque are highly activated, which makes these cells important antigen-presenting cells that develop a specific immune response, in which LDLox is the inducing antigen. As functional changes of cells which participate in the atherogenesis process may occur in the peripheral blood, the objectives of the present study were to evaluate plasma levels of anti-inflammatory and inflammatory cytokines including TNF-α, IFN-γ, interleukin-6 (IL-6), IL-10 and TGF-β in patients with peripheral arteriosclerosis obliterans, to assess the monocyte activation level in peripheral blood through the ability of these cells to release hydrogen peroxide (H2O2) and to develop fungicidal activity against Candida albicans (C. albicans) in vitro.MethodsTNF-α, IFN-γ, IL-6, IL-10 and TGF-β from plasma of patients were detected by ELISA. Monocyte cultures activated in vitro with TNF-alpha and IFN-gamma were evaluated by fungicidal activity against C. albicans by culture plating and Colony Forming Unit (CFU) recovery, and by H2O2 production.ResultsPlasma levels of all cytokines were significantly higher in patients compared to those detected in control subjects. Control group monocytes did not release substantial levels of H2O2 in vitro, but these levels were significantly increased after activation with IFN-γ and TNF-α. Monocytes of patients, before and after activation, responded less than those of control subjects. Similar results were found when fungicidal activity was evaluated. The results seen in patients were always significantly smaller than among control subjects. Conclusions: The results revealed an unresponsiveness of patient monocytes in vitro probably due to the high activation process occurring in vivo as corroborated by high plasma cytokine levels.

Short-term hyperglycemia increases arterial superoxide production and iron dysregulation in atherosclerotic monkeys

The incidence and severity of atherosclerotic vascular disease are increased in diabetic patients, in part because of increased production of reactive oxygen species (ROS). Previously, we found both increased atherosclerosis and arterial protein oxidation 6 months after streptozotocin-induced diabetes in monkeys fed an atherogenic diet, the pattern of which was indicative of redox-active transition metal involvement. The goal of this study was to determine if short-term (1 month) hyperglycemia increases oxidative stress and dysregulates iron metabolism before differences in atherosclerosis. Cynomolgus monkeys with preexisting atherosclerosis were stratified by dietary history and plasma lipids and received either streptozotocin (STZ-DM; n = 10) or vehicle (control; n = 10). One month after diabetes induction, blood and artery samples were collected. There were no differences in plasma lipoprotein cholesterol, arterial cholesterol, and atherosclerosis between control and STZ-DM. However, plasma lipid peroxides were elevated 137% (P < .01); arterial superoxide was increased 47% (P < .05); plasma ferritin, an indicator of whole-body iron stores, was 46% higher (P < .05); and iron deposition within aortic atherosclerotic lesions was more prevalent in STZ-DM compared with controls. Arterial levels of the antioxidant enzymes, superoxide dismutase, catalase, and heme oxygenase-1 were not higher in STZ-DM, although superoxide was higher, suggesting impaired antioxidant response. The increase in ROS before differences in atherosclerosis supports ROS as an initiating event in diabetic vascular disease. Further studies are needed to determine if increases in iron stores and arterial iron deposition promote hydroxyl radical formation from superoxide and accelerate diabetic vascular damage.

Reverse cholesterol transport: from classical view to new insights.

Cholesterol is of vital importance for the human body. It is a constituent for most biological membranes, it is needed for the formation of bile salts, and it is the precursor for steroid hormones and vitamin D. However, the presence of excess cholesterol in cells, and in particular in macrophages in the arterial vessel wall, might be harmful. The accumulation of cholesterol in arteries can lead to atherosclerosis, and in turn, to other cardiovascular diseases. The route that is primarily thought to be responsible for the disposal of cholesterol is called reverse cholesterol transport (RCT). Therefore, RCT is seen as an interesting target for the development of drugs aimed at the prevention of atherosclerosis. Research on RCT has taken off in recent years. In this review, the classical concepts about RCT are discussed, together with new insights about this topic.

Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans

To determine fasting and postprandial metabolism of apolipoprotein B48 (apoB48) remnant lipoproteins in subjects with Type 1 diabetes and the relationship to progressive cardiovascular disease, and to investigate the impact of remnant lipoprotein cholesterol accumulation associated with arterial wall biglycan using a rodent model of Type 1 diabetes. Normolipidaemic subjects (n = 9) with long-standing Type 1 diabetes (and advanced cardiovascular disease) and seven healthy control subjects were studied. Fasting and postprandial apoB48 concentration was determined following a sequential meal challenge. A rodent model of streptozotocin-induced diabetes was used to investigate the ex vivo retention of fluorescent-conjugated remnants. Binding of remnant lipoproteins to human recombinant biglycan was assessed in vitro. A significantly higher concentration of fasting plasma apoB48 remnants was observed in patients with Type 1 diabetes compared with control subjects. Patients with Type 1 diabetes exhibited a greater total plasma apoB48 area under the curve (AUC) and an increased incremental AUC following a second sequential meal compared with control subjects. The arterial retention of remnants ex vivo and associated cholesterol was increased sevenfold in Type 1 diabetes rats relative to controls. Remnants were shown to bind with significant affinity to human biglycan in vitro and a further 2.3-fold increased binding capacity was observed with glycated biglycan. Remnants were shown to colocalize with both arterial biglycan and glycated matrix proteins in the Type 1 diabetes rodent model. Impaired metabolism of remnant lipoproteins associated with enhanced binding to proteoglycans appears to contribute to the arterial cholesterol deposition in Type 1 diabetes. Our findings support the hypothesis that impaired remnant metabolism may contribute to accelerated progression of atherosclerosis in the hyperglycaemic and insulin-deficient state.

N-3 Fatty Acids Decrease Arterial Low-Density Lipoprotein Cholesterol Delivery and Lipoprotein Lipase Levels in Insulin-Resistant Mice

To determine whether n-3 fatty acids (n-3) influence arterial cholesterol delivery and lipoprotein lipase (LpL) levels in insulin-resistant mice. Insulin resistance contributes to risk of cardiovascular disease. It was previously reported that saturated fat (SAT) diets increased, but n-3 diets decreased, arterial low-density lipoprotein (LDL) cholesterol deposition from LDL total and selective uptake; this was associated with increased or decreased arterial LpL, respectively. Insulin receptor transgenic knockout mice (L1) were fed a chow, SAT, or n-3 diet for 12 weeks. Double-fluorescent boron dipyrromethene (BODIPY)-cholesteryl ester (CE) and Alexa dye-labeled human LDL were injected to separately trace LDL-CE and LDL-apolipoprotein B whole particle uptake. In contrast to SAT, n-3 diets markedly reduced all plasma lipids, ameliorating progression of insulin resistance. As opposed to SAT, n-3 reduced arterial LDL uptake, CE deposition, and selective uptake. Disparate patterns of CE deposition between diets were comparable with arterial LpL distribution; SAT induced high LpL levels throughout aortic media; LpL was limited only to intima in n-3-fed mice. n-3 diets diminish arterial LDL-cholesterol deposition in mice with insulin resistance, and this is associated with changes in arterial LpL levels and distribution.

Percepção da doença arterial obstrutiva periférica por pacientes classe I ou II de Fontaine de um Programa de Saúde da Família

CONTEXTO: A doença arterial obstrutiva periférica (DAOP) se destaca por deteriorar a qualidade de vida dos pacientes, quando associada a elevado risco de eventos cardiovasculares e cerebrovasculares. O diagnóstico clínico é sensível e específico, por meio do índice tornozelo-braquial (ITB), que, se precocemente detectado, otimiza o controle dos fatores de risco. OBJETIVO: Avaliar a percepção da DAOP em pacientes classe I ou II de Fontaine assistidos pela Estratégia de Saúde da Família em Pará de Minas (MG), analisando características socioeconômicas e determinantes da qualidade de vida. MÉTODOS: Após cálculo amostral estratificado por gênero e idade, um questionário elaborado para o estudo foi respondido por 123 indivíduos com diagnóstico de DAOP classe I ou II de Fontaine. Para as associações, utilizaram-se testes do c² e exato de Fisher (p&lt;0,05). RESULTADOS: Dos indivíduos que responderam o questionário, 96 (78%) eram do gênero feminino e tinham baixa escolaridade. Observou-se associação entre claudicação intermitente, o sintoma mais frequente da doença, e aperto nas pernas, câimbras, adormecimento dos pés, cansaço, inchaço e agulhadas. Não houve associação com tabagismo, hipertensão arterial sistêmica, diabetes e alteração do colesterol. Dos participantes, 76 (61,8%) nunca ouviram falar da doença, apesar de serem portadores. Dor durante execução de tarefas dentro e fora de casa foi relatada por 48 (39%) indivíduos. A prática de atividade física foi mais recomendada por médico clínico geral - mencionada por 18 (14,6%) indivíduos - sendo que a caminhada, única atividade praticada em níveis recomendados, foi relatada por 102 (27,7%). CONCLUSÃO: É necessário esclarecimento para essa população quanto ao tratamento clínico não-farmacológico para controle das manifestações crônicas irreversíveis. Ressalta-se a relevância da veiculação de informações sobre a evolução silenciosa e sintomatologia da doença.

Continuous Metabolic Syndrome Risk Score, Body Mass Index Percentile, and Leisure Time Physical Activity in American Children

The objective of this study was to determine independent and joint association of body mass index (BMI) percentile and leisure time physical activity (LTPA) with continuous metabolic syndrome (cMetS) risk score in 12- to 17-year-old American children. The 2003 to 2004 US National Health and Nutrition Examination Survey data were used for this investigation. LTPA was determined by self-report. cMetS risk score was calculated using standardized residuals of arterial blood pressure, triglycerides, glucose, waist circumference, and high-density lipoprotein cholesterol. Multiple linear regression analysis was used to evaluate association of BMI percentile and LTPA with cMetS risk score, adjusting for confounders. Increased BMI percentile and LTPA were each associated with increased and decreased cMetS risk score, respectively ((P<.01). There was a gradient of increasing cMetS risk score by BMI percentile cutpoints, from healthy weight (-0.77) to overweight (3.43) and obesity (6.40) ((P<.05). A gradient of decreasing cMetS risk score from sedentary (0.88) to moderate (0.17) and vigorous (-0.42) LTPA levels was also observed (P<.01). The result of this study suggests that promoting LTPA at all levels of weight status may help to reverse the increasing trends of metabolic syndrome in US children.