Fatty Streak Formation Research Articles

Nigella sativa L. improves lipid profile and prevents atherosclerosis: Evidence from an experimental study on hypercholesterolemic rabbits

The effects of Nigella sativa (NS) on lipid profile, C-reactive protein, oxidized LDL, antioxidant capacity, Apo A and Apo B and fatty streak formation in hypercholesterolemic male rabbits were examined. Fifteen rabbits were distributed into three groups of five each [normal diet, hypercholesterolemic diet (1% cholesterol) and hypercholesterolemic diet (1% cholesterol) supplemented with 5% NS]. They received rabbit laboratory chow diet for a period of 8weeks. At the start and end of the study, fasting blood was taken from all animals. NS significantly decreased fatty streak formation as well as total cholesterol (TC) and low-density lipoprotein (LDL) in hypercholesterolemic male rabbits. NS showed positive effects on other factors (triacylglycerol, high-density lipoprotein, C-reactive protein, oxidized LDL, antioxidant capacity, Apo A and Apo B), but these were insignificant. Based on favorable efficiency of NS on TC and LDL reduction and its anti-atherogenic cardioprotective properties, it is suggested using this plant with fat-rich diets simultaneously may reduce their adverse health effects.

Irradiation induces different inflammatory and thrombotic responses in carotid arteries of wildtype C57BL/6J and atherosclerosis-prone ApoE−/− mice

Background and purposeWe have previously shown that irradiation to the carotid arteries of hypercholesterolemic ApoE−/− mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions. We now investigated the mechanism underlying the development of radiation-induced atherosclerosis. Materials and methodsApoE−/− and wildtype C57BL/6J mice received 0, 8 or 14Gy to the neck and the carotid arteries were harvested 1day, 1 or 4weeks later. Immunohistochemical stainings were performed to evaluate well-known inflammatory and thrombotic molecules. A hypothesis-generating approach was used to compare gene expression profiles of irradiated and unirradiated carotid arteries. ResultsBasal levels of endothelial VCAM-1 and thrombomodulin immunoexpression were higher in ApoE−/− mice than in C57BL/6J mice. At 1week after 14Gy VCAM-1 immunoexpression was decreased in ApoE−/− mice, whereas ICAM-1 immunoexpression was decreased at 1 and 4weeks after 14Gy in C57BL/6J mice. Thrombomodulin and tissue factor immunoexpression were elevated at 4weeks after 14Gy in ApoE−/− mice and reduced in C57BL/6J mice. There were no changes in immunoexpression of eNOS, MCP-1 or endoglin. Several canonical pathways were differentially expressed after irradiation, including tight junction pathways, leukocyte extravasation signaling and PI3K/AKT signaling. ConclusionApoE−/− and C57BL/6J mice respond differently to irradiation. The thrombotic pathways were activated after irradiation in ApoE−/− mice only. Genes involved in tight junction regulation were up-regulated in ApoE−/− mice and decreased in C57BL/6J mice. These factors may have contributed to fatty-streak formation in ApoE−/− mice.

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

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

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

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

Proatherogenic Macrophage Activities Are Targeted by the Flavonoid Quercetin

Many studies have demonstrated that the flavonoid quercetin protects against cardiovascular disease (CVD) and related risk factors. Atherosclerosis, the underlying cause of CVD, is also attenuated by oral quercetin administration in animal models. Although macrophages are key players during fatty streak formation and plaque progression and aggravation, little is known about the effects of quercetin on atherogenic macrophages. Here, we report that primary bone marrow-derived macrophages internalized less oxidized low-density lipoprotein (oxLDL) and accumulated less intracellular cholesterol in the presence of quercetin. This reduction of foam cell formation correlated with reduced surface expression of the oxLDL receptor CD36. Quercetin also targeted the lipopolysaccharide-dependent, oxLDL-independent pathway of lipid droplet formation in macrophages. In oxLDL-stimulated macrophages, quercetin inhibited reactive oxygen species production and interleukin (IL)-6 secretion. In a system that evaluated cholesterol crystal-induced IL-1β secretion via nucleotide-binding domain and leucine-rich repeat containing protein 3 inflammasome activation, quercetin also exhibited an inhibitory effect. Dyslipidemic apolipoprotein E-deficient mice chronically treated with intraperitoneal quercetin injections had smaller atheromatous lesions, reduced lipid deposition, and less macrophage and T cell inflammatory infiltrate in the aortic roots than vehicle-treated animals. Serum levels of total cholesterol and the lipid peroxidation product malondialdehyde were also reduced in these mice. Our results demonstrate that quercetin interferes with both key proatherogenic activities of macrophages, namely foam cell formation and pro-oxidant/proinflammatory responses, and these effects may explain the atheroprotective properties of this common flavonoid.

Hyperinsulinemia may have a protective role in the early stages of atherosclerosis in rabbit model of hypercholesterolemia

BackgroundHypercholesterolemia causes inflammation and insulin resistance in the vasculature. Previous data suggest that vascular endothelium is a physiological target of insulin. Dyslipidemia and atherosclerosis are disorders with endothelial dysfunction that are associated with an increased production of superoxide anion, and early deficit of nitric oxide (NO) production. We examined alteration of plasma levels of insulin, C-reactive protein (CRP) and total NO metabolites (NOx), as well as fatty streak formation in the rabbit model of hypercholesterolemia.MethodsWhite male rabbits were fed either a high-cholesterol diet (HC; 1% cholesterol, n = 6) or control diet (c, n = 6) for one month. The serum levels of Cholesterol, LDL, HDL, NOx, insulin and CRP were measured before and after study. By the end of study, rabbits' aorta was explored for fatty streak formation.ResultsThe cholesterol-rich diet induced a significant increase in total cholesterol, LDL, and HDL as well as fatty streak lesions in HC group while there were no significant changes of these parameters in control group (p <0.05). There was significant difference in plasma levels of CRP, insulin and total NO metabolite between two groups of experiment. Negative significant correlation of CRP and insulin also was observed in HC rabbits (r = −0.99, p <0.05).ConclusionParallel NOx and insulin increment and negative correlation of CRP and insulin in HC rabbits may be suggestive a protective role of hyperinsulinemia in early atherosclerosis.

Control of growth and inflammatory response of macrophages and foam cells with nanotopography

Macrophages play an important role in modulating the immune function of the human body, while foam cells differentiated from macrophages with subsequent fatty streak formation play a key role in atherosclerosis. We hypothesized that nanotopography modulates the behavior and function of macrophages and foam cells without bioactive agent. In the present study, nanodot arrays ranging from 10‐ to 200‐nm were used to evaluate the growth and function of macrophages and foam cells. In the quantitative analysis, the cell adhesion area in macrophages increased with 10- to 50-nm nanodot arrays compared to the flat surface, while it decreased with 100- and 200-nm nanodot arrays. A similar trend of adhesion was observed in foam cells. Immunostaining, specific to vinculin and actin filaments, indicated that a 50-nm surface promoted cell adhesion and cytoskeleton organization. On the contrary, 200-nm surfaces hindered cell adhesion and cytoskeleton organization. Further, based on quantitative real-time polymerase chain reaction data, expression of inflammatory genes was upregulated for the 100- and 200-nm surfaces in macrophages and foam cells. This suggests that nanodots of 100‐ and 200‐nm triggered immune inflammatory stress response. In summary, nanotopography controls cell morphology, adhesions, and proliferation. By adjusting the nanodot diameter, we could modulate the growth and expression of function-related genes in the macrophages and foam cell system. The nanotopography-mediated control of cell growth and morphology provides potential insight for designing cardiovascular implants.

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

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

Macrophages, lipid metabolism and gene expression in atherogenesis: a therapeutic target of the future?

AbsractCardiovascular disease results in more deaths globally than any other ailment. A major contributing factor to its pathology is atherosclerosis; an inflammatory disorder characterized by the development of fibrotic plaques within the arterial walls. Key to the progression of atherosclerosis are macrophages that contribute to plaque development by transforming into lipid-loaded foam cells upon internalization of modified lipoproteins. Accumulation of such foam cells in the arterial wall initiates the formation of fatty streaks that subsequently develop into advanced plaques that are prone to rupture. Clearly, macrophage lipid metabolism and foam cell biology represent a key avenue of research during the ongoing search for novel therapeutic targets that can be used in the clinical intervention of atherosclerosis. In this article, we aim to summarize the current status of research on macrophages, lipid metabolism and gene expression in relation to atherogenesis and both current and potential future therapies.

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

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

Vasculitis, Atherosclerosis, and Altered HDL Composition in Heme-Oxygenase-1-Knockout Mice

To elucidate roles of heme oxygenase-1 (HO-1) in cardiovascular system, we have analyzed one-year-old HO-1-knockout mice. Homozygous HO-1-knockout mice had severe aortitis and coronary arteritis with mononuclear cellular infiltration and fatty streak formation even on a standard chow diet. Levels of plasma total cholesterol and HDL were similar among the three genotypes. However, homozygous HO-1-knockout mice had lower body weight and plasma triglyceride. HO-1-deficiency resulted in alteration of the composition of HDL. The ratio of apolipoprotein AI to AII in HO-1-knockout mice was reduced about 10-fold as compared to wild-type mice. In addition, paraoxonase, an enzyme against oxidative stress, was reduced less than 50% in HO-1-knockout mice. The knockout mice also exhibited significant elevation of plasma lipid hydroperoxides. This study using aged HO-1-knockout mice strengthened the idea that HO-1 functions to suppress systemic inflammation in artery wall and prevents plasma lipid peroxidation.

Abstract 9878: Pioglitazone Ameliorates Atherosclerotic Lesions with the Modification of the Balance of Effector and Regulatory T Cells in Apolipoprotein E Deficient Mice

BACKGROUND: Pioglitazone (PIO) affects T cell-mediated immunity through actions of peroxisome proliferator activated receptor γ. Effector and regulatory T cells control the development of atherosclerosis, a chronic inflammatory disease affecting the arterial blood vessels. PURPOSE: The aim of this study was to examine whether PIO ameliorates atherosclerosis by altering the balance of effector and regulatory T cells. METHODS AND RESULTS: To explore the effect of PIO on early and advanced atherosclerosis, apolipoprotein E deficient (ApoE-/-)mice were fed western diet and received PIO (20mg/kg/day) by gastric gavage at 6 or 14 weeks of age, respectively for 8 weeks (each n=12). Data showed that PIO markedly inhibited early fatty streak formation. Although the advanced fibrofatty plaque sizes were not significantly reduced, the numbers of smooth muscle cells within lesions were increased and higher collagen concentrations were produced by PIO. In general, macrophage expression in lesions was decreased by PIO. Additionally, the expression of Foxp3+ cells (regulatory T) was increased in lesions and spleens in mice at all PIO treatment stages, whereas the CD4+interferon-γ+/CD4+interleukin-4+cell ratios were reduced. CONCLUSION: PIO inhibited early atherosclerotic lesion formation and increased the stability of advanced atherosclerotic plaques in ApoE-/- mice, which was associated with altering the balance of effector and regulatory T cells.

The effects of concurrent hydroalcoholic extract of Amaranthus caudatus L. and Hypericum perforatum L. of fatty streak formation in hypercholesterolemic animals

Hypercholesterolemia, a high cholesterol diet and oxidative stress increase serum low density lipoprotein (LDL) levels resulting in increased risk for development of atherosclerosis. Antioxidants play an important role in inhibiting and scavenging radicals, thus providing protection to humans against contagious and degenerative diseases. The aim of this study was to assess the anti-fatty streak effects of concurrent hydroalcoholic extracts of Amaranthus caudatus L. (A. caudatus) and Hypericum perforatum L. (H. perforatum) as this were investigated in hypercholesterolemic rabbits and was compared with lovastatin. Rabbits were randomly divided into four groups which were fed with normal diet (control), high-cholesterol diet (hypercholesterolemic control group), high-cholesterol + concurrent hydroalcoholic extracts of A. caudatus (75 mg/kg daily) and H. perforatum (75 mg/kg daily) (treatment group), and high-cholesterol + lovastatin (10 mg/kg daily) (treatment group) for 60th days and then blood samples were obtained to measure plasma cholesterol, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoproteinA (apoA), apolipoproteinB (apoB), malondialdehyde (MDA), C-reactive protein (CRP), Ox-LDL and AI aorta was also obtained for histological evaluation. The observation showed decrease in plasma cholesterol, TG, HDL, LDL, apoB, CRP, MDA, OX-LDL, AI and increased apoA and HDL between treatment groups and hypercholesterolemic control groups (P>0.05). The mean size of produced fatty streak also showed significant reduction in the treatment groupIII compared to the hypercholesterolemic group (P<0.05). This results showed that combination of hydroalcoholic extracts of A. caudatus and H. perforatum has anti-fatty streak effects in hypercholesterolemic rabbits. Key words: Atherosclerosis, Amaranthus, Hypericum.

Anti atherosclerotic effects of verjuice on hypocholesterolemic rabbits

The aim of the present study was to evaluate the effects of verjuice on atherosclerosis risk factors in rabbits fed a cholesterol-rich diet for how long. Two New Zealand rabbits were used for this study which lasted 8 weeks. The rabbits were divided to four groups and treated as follows normal diet, cholesterol-rich diet, cholesterol-rich diet supplemented with 5 ml verjuice and cholesterol-rich diet supplemented with 10 ml verjuice. The low density lipoprotein-cholesterol (LDL-C), malondialdehyde (MDA), oxidized LDL (ox-LDL), nitrite, nitrate; factor VII, fibrinogen and C-reactive protein (CRP) were measured before and after experimental feeding. In all groups, fatty streak formation in right and left coronary arteries were determined at the end of the study. Administration of low (5 ml) and high (10 ml) dose of verjuice significantly lowered the levels of fibrinogen (p < 0.05) and atherosclerotic lesion in right and left coronary arteries (p < 0.05). However, the serum level of nitrite and nitrate increased in both verjuice supplemented groups. Administration of 10 ml verjuice could significantly reduce the amount of MDA, ox-LDL, LDL-C (p < 0.05). No significant effects were noted for CRP and factor VII after consumption of both doses of verjuice. We conclude that verjuice could reduce some atherosclerotic risk factors in long term treatment.

Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality

ObjectiveFetal exposure to maternal hypercholesterolemia increases the extent of fatty-streak formation in fetal aortas as well as the rate of progression, and may therefore increase coronary heart disease (CHD) risk later in life. We hypothesized that the risk of CHD in untreated individuals with familial hypercholesterolemia (FH) is more extreme when the disease is transmitted maternally. MethodsIn a large Dutch pedigree carrying the V408M mutation in the low-density lipoprotein (LDL) receptor gene, 161 individuals over seven generations were identified for which FH status and parent of origin of FH were known. We calculated standardized mortality ratios (SMR) and compared the consequences of maternal and paternal inheritance of FH by Poisson regression analysis. ResultsMaternally inherited FH was associated with significantly higher excess mortality than FH transmitted by fathers (relative risk 2.2; p=0.048): the SMR of maternal inheritance was 2.49 (95% confidence interval (CI) 1.45–3.99; p=0.001), whereas it was not significantly increased in paternally inherited FH (SMR 1.30, 95% CI 0.65–2.32; p=0.234). ConclusionMortality rates are more increased when FH is inherited through the mother, supporting the fetal origin of adulthood disease hypothesis with all cause death, the most indisputable outcome measure. Future research should explore safe options for cholesterol-lowering therapy of pregnant women with FH in order to prevent unfavourable (epigenetic) consequences leading to atherosclerosis in their children.

A Multiscale Model of Atherosclerotic Plaque Formation at Its Early Stage

A multiscale model of atherosclerotic plaque formation at its early stage has been developed in order to integrate the various phenomena leading to fatty streak formation. The different scales considered in this model are in both the spatial domain (from cellular to organism level) and the time domain (from seconds to months). The cellular level was considered by modeling the transport and chemical interactions of low-density lipoproteins (LDL) and other agents in a stenosed artery. This was linked to arterial thickening (organ level). Mean blood LDL level (organism level) was selected as one of the critical factors for atherosclerotic formation along with wall shear stress (WSS) exerted on the endothelium (the inner portion of the artery). It was observed that plaque location was dependent on WSS and that plaque size, number, and growth was dependent on mean blood LDL levels as well.

59 Short term elevation of cholesterol level in neonatal life and long term changes in aortic stiffness: insights from use of intravenous lipids

<h3>Introduction</h3> Offspring born to hypercholesterolaemic mothers have increased fatty streak formation in the fetal aorta, which persists into adolescence. To understand whether exposure to elevated cholesterol in early life, independent of a maternal history of hypercholesterolaemia, also has a long-term impact on the cardiovascular system we studied the vascular phenotype of adults in whom cholesterol levels were artificially elevated for a short period postnatally. <h3>Methods</h3> We prospectively followed-up 102 subjects born premature now aged 23 to 28 years. Individuals exposed to maternal hypercholesterolaemia were excluded. 18 received intravenous (IV) lipids during the first nine weeks of life and were matched 2:1 for pregnancy and early life complications, age, sex, birthweight and gestational age with controls that did not receive IV lipids. Aortic pulse wave velocity (aPWV), regional aortic distensibility, left ventricular mass and ejection fraction were determined by cardiovascular magnetic resonance. Detailed lifestyle information and anthropometric measurements were collected during childhood and adolescence. Metabolic parameters were measured multiple times per week for the first 9 weeks of life and again at follow-up visits. <h3>Results</h3> Individuals that received IV lipids achieved significantly higher maximum cholesterol levels during the first 9 weeks of life than those that did not (mean±SD=4.38±1.65 vs 3.12±0.78 mmol/l, p=0.006). Dose given and number of days on IV lipids also associated with maximum cholesterol level during this period (r=0.557, p&lt;0.001 and r=0.567, p&lt;0.001, respectively). There was a graded relation between the maximum elevation in circulating cholesterol postnatally and aortic stiffness (aPWV) in young adulthood (r=0.596, p&lt;0.001). The greatest increase in stiffness was seen in the abdominal aorta, where distensibility was significantly reduced in the group that received IV lipids (mean±SD=9.74±4.27 vs 12.91±4.11/mm Hg×10³, p=0.012). There were no differences between the groups in other vascular or left ventricular measures. In a stepwise regression model, maximum cholesterol level achieved in the first few weeks of life was an independent predictor of aPWV in young adulthood (β=0.596, p&lt;0.001) and accounted for 30.9% of the variance in hierarchical multiple regression (β=0.584, p&lt;0.001). <h3>Conclusions</h3> Brief artificial elevation of cholesterol level in immediate postnatal life is associated with long term changes in aortic function independent of later cholesterol levels. The association is graded depending on the degree of elevation of circulating cholesterol. High cholesterol exposure during sensitive periods of early postnatal life may have long term impacts on the cardiovascular system.

Reduces cholesterol induced atherosclerotic lesions in aorta artery in hypercholesterolemic rabbits

Atherosclerosis is the leading cause of death in developed countries with many proved risk factors. Vinegar has been proved to have some medical uses and some potential protective effects on atherosclerosis. In this study, effects of vinegar on various risk factors of atherosclerosis and development of atherosclerosis in hypercholesterolemic rabbit have investigated. Rabbits were assigned to four groups and each group received one of experimental diets: normal diet, high cholesterol diet (1% cholesterol), 1% cholesterol supplemented with 5 ml vinegar and 1% cholesterol supplemented with 10 ml vinegar for 8 weeks. Blood samples were collected before and after 8 weeks of experimental diets for measurement of serum C-reactive protein (CRP), nitrite, nitrate, apolipoprotein A (ApoA 1) and apolipoprotein B (ApoB 100 ), total cholesterol (TC), fibrinogen and factor VII. At the end of study, fatty streak formation in aorta was determined in all groups. Using vinegar (5 and 10 ml) with hypercholesterolemic diet caused significant reduction in CRP, fibrinogen, factor VII, ApoB 100 , ApoB/ApoA ratio, TC levels, atherosclerotic lesions in aorta and increased nitrite and nitrate in comparison with hypercholesterolemic diet. Vinegar did not significantly change ApoA 1 level compared to high cholesterol diet. These results suggest that vinegar reduced atherosclerosis processes in high cholesterol diet fed animals. More studies are needed to find the exact mechanisms of action.

Role of Heparanase on Hepatic Uptake of Intestinal Derived Lipoprotein and Fatty Streak Formation in Mice

BackgroundHeparanase modulates the level of heparan sulfate proteoglycans (HSPGs) which have an important role in multiple cellular processes. Recent studies indicate that HSPGs have an important function in hepatic lipoprotein handling and processes involving removal of lipoprotein particles.Principal FindingsTo determine the effects of decreased HSPGs chain length on lipoprotein metabolism and atherosclerosis, transgenic mice over-expressing the human heparanase gene were studied.Hepatic lipid uptake in hpa-Tg mice were evaluated by giving transgenic mice oral fat loads and labeled retinol. Sections of aorta from mice over-expressing heparanase (hpa-Tg) and controls (C57/BL6) fed an atherogenic diet were examined for evidence of atherosclerosis. Heparanase over-expression results in reduced hepatic clearance of postprandial lipoproteins and higher levels of fasting and postprandial serum triglycerides. Heparanase over-expression also induces formation of fatty streaks in the aorta. The mean lesion cross-sectional area in heparanase over-expressing mice was almost 6 times higher when compared to control mice (23,984 µm2±5,922 vs. 4,189 µm2±1,130, p<0.001).ConclusionsOver-expression of heparanase demonstrates the importance of HSPGs for the uptake of intestinal derived lipoproteins and its role in the formation of fatty streaks.

Lipoprotein associated phospholipase A2: role in atherosclerosis and utility as a biomarker for cardiovascular risk

Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cell, fatty streak, and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Lipoprotein-associated phospholipase A2 (Lp-PLA2) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA2 measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA2 are in development and show considerable promise, including darapladib, a specific molecular inhibitor of the enzyme. In addition to substantially inhibiting Lp-PLA2 activity, darapladib reduces progression of the necrotic core volume of human coronary artery atheromatous plaque. The growing body of evidence points to an important role and utility for Lp-PLA2 testing in preventive and personalized clinical medicine.