Hypercholesterolemic Group Research Articles

Virtual exploration of early stage atherosclerosis.

Biological mechanisms contributing to atherogenesis are multiple and complex. The early stage of atherosclerosis (AS) is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells (FC). To address the difficulty to explore the dynamics of interactions that controls this process, this study aimed to develop a model of agents and infer on the most influential cell- and molecule-related parameters. FC started to accumulate after six to eight months of simulated hypercholesterolemia. A sensitivity analysis revealed the strong influence of LDL oxidation rate on the risk of FC creation, which was exploited to model the antioxidant effect of statins. Combined with an empirical simulation of the drug ability to decrease the level of LDL, the virtual statins treatment led to reductions of oxidized LDL levels similar to reductions measured in vivo. An Open source software was used to develop the agent-based model of early AS. Two different concentrations of LDL agents were imposed in the intima layer to simulate healthy and hypercholesterolemia groups of 'virtual patients'. The interactions programmed between molecules and cells were based on experiments and models reported in the literature. A factorial sensitivity analysis explored the respective effects of the less documented model parameters as (i) agent migration speed, (ii) LDL oxidation rate and (iii) concentration of autoantibody agents. Finally, the response of the model to known perturbations was assessed by introducing statins agents, able to reduce the oxidation rate of LDL agents and the LDL boundary concentrations. jerome.noailly@upf.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Effect of pathological conditions on peritoneal macrophage glycosaminoglycans: Impact on cytoadherence

Glycosaminoglycans (GAGs) have a plethora of functions to play. They are widely present in extracellular matrix, cell surface and inside the cell. During pathological conditions remodeling of GAGs leads to modifications in their structure and functions. In the present work, peritoneal macrophages were isolated from normal, diabetic, and diet-induced hypercholesterolemic rats and evaluated in terms of GAGs and cytoadherence to various extracellular matrix (ECM) components. Peritoneal macrophages are known to play important roles in the control of infection and inflammation. Isolated GAGs were characterized as belonging to heparan sulfate/heparin class. There were quantitative changes in sulfated GAGs in diabetic and hypercholesterolemic groups when compared to normal rats. Dose-dependent changes in cytoadherence were observed only with respect to fibronectin in LPS-activated macrophages from diabetic animals but not with laminin and type IV collagen when compared to macrophages from normal rats. Cytoadherence was significantly decreased on treatment with heparinase indicating that cytoadherence was at least partly mediated by heparan sulfate/heparin class of GAGs. Global disaccharide composition analysis showed that GAGs from macrophages of diabetic animals had higher sulfation ratio when compared to that of control and hypercholesterolemic animals.

Neuroprotective Effects of Low-Dose Statins in the Retinal Ultrastructure of Hypercholesterolemic Rabbits.

To evaluate the pleiotropic effects to statins, we analyze the qualitative and quantitative retinal changes in hypercholesterolemic rabbits after a low-dosage statin treatment. For this purpose, New Zealand rabbits were split into three groups: control (G0; n = 10), fed a standard diet; hypercholesterolemic (G1; n = 8), fed a 0.5% cholesterol-enriched diet for 8 months; and statins (G2; n = 8), fed a 0.5% cholesterol-enriched diet for 8 months, together with the administration of statin (pravastatin or fluvastatin sodium) at a dose of 2 mg / kg / day each diet. The retinas were analyzed by transmission electron microscopy and immunohistochemistry (glial fibrillary acidic protein). The retinal thickness of nuclear and plexiform layers were quantified in semi-thin sections. The results revealed that the low-statin-treated rabbits in comparison with the hypercholesterolemic group showed: i) a more preserved structure in all retinal layers; ii) a significant reduction in retinal thickness; iii) a decrease in cell death in the nuclear-and ganglion-cell layers; iv) a reduction of hydropic degeneration in the plexiform and nerve-fiber layers; v) a preservation of astrocytes and of the retinal area occupied by them; and vi) a better-preserved retinal vascular structure. Our findings indicate that low doses of statins can prevent retinal degeneration, acting on retinal macroglia, neurons and retinal vessels, despite that hypercholesterolemia remained unchanged. Thus, the pleiotropic effects of the statins may help safeguard the retinal ultrastructure.

Cilostazol exerts antiplatelet and anti-inflammatory effects through AMPK activation and NF-kB inhibition on hypercholesterolemic rats.

This work presents a model of rats fed a high-cholesterol diet, receiving a long-term oral administration of cilostazol, a PDE3-inhibitor. The aim of this study was to evaluate the molecular mechanisms by which cilostazol interferes with platelets signaling pathways to avoid atherosclerosis early development. Male Wistar rats were divided into 3 groups: Control group received standard rat chow (C), hypercholesterolemic group (HCD), and HCD+CIL (cilostazol group) received hypercholesterolemic diet for 45 days. HCD+CIL group received cilostazol (30 mg/kg/p.o.) once daily in the last 15 days. Platelet aggregation, lipid profile, lipid peroxidation, and cytokine serum levels were assessed. Expression of P-selectin, CD40L, PKC-α, IkB-α, and iNOS and activation of AMPK, NF-κB, and eNOS in the platelets were assessed using Western blot analysis. Cilostazol reduced the levels of total cholesterol (361.0 ± 12.8 vs. 111.5 ± 1.6 mg/dL), triglycerides (186.9 ± 17.7 vs. 55.4 ±3.1 mg/dL), cLDL (330.9 ± 9.7 vs. 61.5 ± 3.5 mg/dL), cVLDL (45.0 ± 4.6 vs. 11.1 ± 0.6 mg/dL), and malondialdehyde (9.4 ± 0.5 vs. 3.2 ± 0.3 nmol/mL) compared to the HCD group. Cilostazol presented antiplatelet properties and decreased inflammatory markers levels. These effects seem to be related to AMPK activation, NF-kB inhibition, and eNOS activation.

Acute effect of rosiglitazone on relaxation responses in hypercholesterolemic corpus cavernosum

Thiazolidinediones (TZDs) improve vascular endothelial dysfunction through non-genomic effects of peroxisomal proliferator-activated receptor γ. This study investigated the acute effect of one of the TZD, rosiglitazone, on endothelium-dependent relaxation response of corpus cavernosum (CC) in hypercholesterolemic rabbits. New Zealand rabbits were divided into two groups randomly as control and cholesterol groups. Hypercholesterolemia was induced by feeding rabbits with 2% cholesterol diet (w/w) for 6 weeks. Endothelium-dependent and -independent relaxation response of CC were evaluated in the presence of rosiglitazone by organ bath studies with cumulative doses of acetylcholine (Ach) and sodium nitroprusside (SNP). Maximal relaxation (Emax) response to Ach significantly decreased owing to hypercholesterolemia in CC tissues. However, in vitro incubation of rosiglitazone with different concentrations (0.1, 1 and 10 μm) did not improve the Ach-dependent Emax responses in hypercholesterolemic rabbit CC. Surprisingly, rosiglitazone caused a significant decrease in Ach-dependent relaxation in healthy CC. Emax responses to SNP did not differ in the presence of rosiglitazone in both the control and hypercholesterolemic groups. Rosiglitazone does not improve hypercholesterolemia-induced endothelial dysfunction in CC tissues while it dose-dependently impairs endothelium-dependent relaxation in healthy CC tissue.

The Increase Activity of Lipoprotein Lipase (LPL) Enzyme and Histophatological Changes of Liver of Hypercholesterolemic Rat (Rattus norvegicus) Induced by Ethanolic Extract of Ant Plant (Myrmecodia sp.)

This study was aimed to find out the effect of ethanolic extract of ant plant (Myrmecodia sp.) to increase the activity of enzyme lipoprotein lipase (LPL) serum and to observe the histopathological changes of hypercholesterolemic rat liver. This study used 20 male rats grouped into 4treatment groups, namely negative control group (K1), hypercholesterolemic group (K2), and hypercholesterolemic group that administered withethanolic extract of ant plant 100 (K3) and 200 mg/kg bw (K4). The LPL enzyme activity were measured by the titration method andhistopatological changes of liver were observed by calculated fatty degeneration and fatty infiltration. The data were analyzed using one wayanova followed by Duncan test. The average of LPL enzyme activity on group K1, K2, K3, and K4 were 0.80±0.06, 0.45±0.10, 0.83±0.11, and0.76±0.03 unit, respectively. The average number of fatty degeneration on hepatocyte and fatty infiltration were 1.80±0.83, 3.60±1.14, 23.00±1.22, and 40.20±1.30; and 9.20±0.84, 16.40±1.14, 2.60±0.54, and 4.80±0.83, respectively. The results showed that theraphy ethanolic extract ofant plant effects significantly (P<0.01) on the increase of enzyme LPL and improve liver damage in hypercholesterolemic male rats. To concludethe administration of ethanolic extract of ant plant increases the LPL enzyme activity and improves liver damage on hyperch olesterolemic rats.Key words: Myrmecodia sp., LPL activity, histopathological liver, hypercholesterolemia

Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes

1. Our objective is to investigate the alterations of hepatic drug transporters and metabolizing enzymes in hypercholesterolemia. Male Sprague–Dawley rats were fed high-cholesterol chows for 8 weeks to induce hypercholesterolemia. Protein levels of hepatic drug transporters and metabolizing enzymes were analyzed by iTRAQ labeling coupled with LC TRIPLE-TOF.2. Total 239 differentially expressed proteins were identified using proteomic analysis. Among those, protein levels of hepatic drug transporters (MRP2, ABCD3, OAT2, SLC25A12, SCL38A3, SLC2A2 and SLC25A5) and metabolizing enzymes (CYP2B3, CYP2C7, CYP2C11, CYP2C13, CYP4A2 and UGT2B) were markedly reduced, but the levels of CYP2C6 and CYP2E1 were increased in hypercholesterolemia group compared to control. Decreased expressions of drug transporters MRP2 and OAT2 were further confirmed by real time quantitative PCR (RT-qPCR) and western blot.3. Ingenuity pathway analysis revealed that these differentially expressed proteins were regulated by various signaling pathways including nuclear receptors and inflammatory cytokines. One of the nuclear receptor candidates, liver X receptor alpha (LXRα), was further validated by RT-qPCR and western blot. Additionally, LXRα agonist T0901317 rescued the reduced expressions of MRP2 and OAT2 in HepG2 cells in hypercholesterolemic serum treatment.4. Our present results indicated that hypercholesterolemia affected the expressions of various drug transporters and metabolizing enzymes in liver via nuclear receptors pathway. Especially, decreased function of LXRα contributes to the reduced expressions of MRP2 and OAT2.

Effects of resveratrol on the alterations of cavernosal eNOS and LOX-1 expression in the hypercholesterolemic condition: a preliminary study.

The aim of this study was to determine the effects of resveratrol on the alterations of cavernosal eNOS and LOX-1 mRNA expression in the hypercholesterolemic condition. Twenty-one New Zealand white male rabbits were separated into three groups. Rabbits were fed with a normal dietary intake for the control group and a 2% cholesterol diet for the hypercholesterolemia and resveratrol groups for 6 weeks. Resveratrol 4 mg/kg daily was administered for the resveratrol group. Cavernosal LOX-1 and eNOS mRNA expressions were determined with real-time RT-PCR in all groups. The statistical analysis was performed with the Kruskal-Wallis and Mann-Whitney U tests. We found no difference between mean LOX-1 mRNA expression levels in the three groups. Lower mean eNOS mRNA expression level was determined in the hypercholesterolemia group when compared with the control group (P = 0.011). Mean eNOS mRNA expression level in the resveratrol group was similar to that in the control group but significantly higher than that in the hypercholesterolemia group (P < 0.001). This preliminary study demonstrates the beneficial effects of resveratrol on cavernosal eNOS expression. The presence of cavernosal LOX-1 expression was also shown for the first time. Resveratrol may be an alternative option in hypercholesterolemic erectile dysfunction with further studies supporting its beneficial effects on the corpus cavernosum.

A Comparative Study of Some Functional Properties of Lactobacillus and Enterococcus Isolated from Feces of Normo and Hyper-Cholesterolemic Humans

There have been reports of an association between an imbalance of gastrointestinal microbiota and several kinds of diseases, mainly metabolic diseases. Lactobacillus and Enterococcus are two genera that form part of the native gastrointestinal microbiota. In this work, we isolated, identified and characterized 26 strains of Lactobacillus and 23 strains of Enterococcus from the feces of normo and hypercholesterolemic humans. We compared the behavior exhibited by all strains at acid pH and in presence of bile salts, their sensitivity to antibiotics, and their ability to hydrolyze bile salts and to reduce cholesterol in vitro. The highest percentage of all isolated and characterized Lactobacillus strains was from the normocolesterolemic group; in the hypercholesterolemic group, most strains belonged to the Enterococcus genus. The Lactobacillus strains showed greater capacity to reduce cholesterol levels; although this capacity has been related to bile salt hydrolase activity, four of the strains we isolated showed no such activity, but still reduced cholesterol. All strains of both genera isolated from normocholesterolemic participants showed a highest rate of cholesterol reduction than those isolated from hypercholesterolemic participants. Furthermore, the Lactobacillus strains showed greater resistance at pH 2.0, while strains of both genera showed similar survival rates at pH 3.0 and in the presence of bile salts after 24 h. These results support the evidence that a microbial imbalance involving the depletion of beneficial bacteria could be detrimental to the health of the host.

A study on the effects of the alcoholic extract of the aerial parts of Echinophora Platyloba on the activity of pituitary-gonadal axis in hypercholesterolemic rats

The present experimental study was carried out to examine the effects of the alcoholic extract of the aerial parts of Echinophora platyloba on prolactin (PRL) levels and the activity of pituitary-gonadal axis in animal model. Forthy male wistar rats were divided into five groups: control group with normal diet, hypercholesterolemic group with fat diet, and three experimental groups which received Echinophora platyloba alcoholic extract as gavage at the minimum dose of 100, the average dose of 200, and the maximum dose of 400 mg/kgbw over a period of 21 days. At the end of the period, to assess the levels of PRL, cholesterol, testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), blood samples were taken and data were analyzed. The levels of testosterone and cholesterol in hypercholesterolemic group compared to the control, showed a significant decrease and increase, respectively (P≤0.05). Echinophora platyloba extract caused significant increases in testosterone, PRL and a significant decrease in cholesterol levels (P≤0.05), however, it had no significant effect on the levels of LH and FSH. The results of this study showed that the consumption of alcoholic extract of Echinophora platyloba is effective in reducing serum cholesterol, increasing testosterone production and enhancing sexual performance.

Effects of Giving Pedada Fruit Flour (PFF) on Digesta Profile and SCFAs Hypercholesterolemic Rats

Pedada Fruit Flour (PFF) contains 8.9% of pectin, it includes one type of soluble dietary fiber. It has hypocholesterelemic property. The effect of PFF to the digesta cholesterol profile, and production of SCFA (short chain fatty acids) has not been done before. The aim of this study is to determine the impact of giving PFF on digesta profile and short chain fatty acids (SCFAs). Twenty-five Wistar rats were divided into 5 treatment groups consist of two normal control, hypercholesterolemic group, and 3 treatment of hypercholesterolemic groups feed were supplemented with 3, 6 and 9% PFF. Feeding was given for 28 days, on the 30 th day surgery was done to take the digesta, then performed an analysis of digesta profile includes weight, water content, cholesterol and SCFAs levels. The results showed that supplementation of 6 and 9% PFF had significant effect on weight, water contents and cholesterol of digesta with the highest propionic: acetic acid ratio in the group treated with supplementation of 9% PFF (0.46) followed by supplementation group 6% and 3% i.e., 0.41 and 0.38, respectively. The ratio of propionic: acetic acid can reduce of serum cholesterol levels.

Effect of a hypercholesterolemia as a starting factor on spinal degeneration in rabbits and role of Vitamin E (α-tocopherol).

Background:To identify the role of the hypercholesterolemia as a starting factor in discovertebral degeneration that ultimately causes lower back pain, and investigate the role of Vitamin E in this process.Methods:The rabbits (n = 32) were divided into two broad experimental groups: A control group, and a hypercholesterolemia group, namely cholesterol, and cholesterol plus Vitamin E groups and they were fed sequentially for 4 or 8 weeks. Serum cholesterol and Vitamin E (α-tocopherol) levels were determined; vascular tissue was prepared for histopathological analyses and vertebra was decalcified for the study.Results:Cholesterol diet group resulted approximately 44-fold of increase plasma cholesterol levels over the 4-week control values. Additional supplementation with Vitamin E group induced a plasma cholesterol level increase of only 37-fold as compared to the control group. In the cholesterol groups, light microscope examination revealed atherosclerotic plaque in major arteries. However, in the cholesterol plus Vitamin E treatment groups, no lipid accumulation or foam cell formation was visible in the abdominal aorta and vertebral segmental artery. In histopathological examination, we found degenerative changes in the discovertebral unit in cholesterol treated groups.Conclusion:Hypercholesterolemia causes fat accumulation in the disc endplate and vertebral body that causes blood supply disturbances which might be a starting factor of discovertebral degeneration. This event was not reversed by the elimination of cholesterol from the diet. Vitamin E supplementation was not effective in reducing fat accumulation in vertebral bone marrow. As a result, we conclude that degeneration of the discovertebral unit is not related to atherosclerotic changes in the major blood vessels.

Lipid Lowering Effects of Hydroalcoholic Extract of Anethum graveolens L. and Dill Tablet in High Cholesterol Fed Hamsters

Objective. This study was aimed to determine the effect of Anethum graveolens extract and Anethum graveolens (dill) tablet on lipid profile, liver enzymes, and gene expression and enzymatic activity of HMG-CoA reductase in high cholesterol fed hamsters. Materials and Methods. Golden Syrian male hamsters (130 ± 10 g) were randomly divided into 6 groups (n = 6) and received daily the following: group 1 received chow + 2% cholesterol + 0.5% cholic acid (HCD), groups 2 and 3 received HCD diet plus 100 and 200 mg/kg hydroalcoholic extract of dill, respectively, and groups 4 and 5 received HCD diet plus 100 and 200 mg/kg dill tablet, respectively. Group 6 received only chow. After 1 month feeding serum biochemical factors were determined. HMG-CoA reductase mRNA level was measured (real-time PCR) and its activity was determined spectrophotometrically. Results. Compared with hypercholesterolemic group 1, lipid profile, blood glucose, and liver enzymes significantly decreased in all dill tablet or dill extract treated groups (p < 0.05). The changes in HMG-CoA reductase gene expression level and enzyme activity significantly reduced in animals that received 200 mg/kg of extract or tablet. Conclusion. Dill extract and dill tablet showed potential hypocholesterolemic properties in hamsters by inhibition of HMG-CoA reductase activity.

Aktivitas Hipolipidemik dan Indeks Aterogenik yang Rendah Ekstrak Air Daun Tapak Dara pada Tikus Hiperkolesterolemia

Catharanthus roseus is one plant recognized as medical potential which can decrease cholesterol. Thepresent study was carried out to evaluate the effect of aqueous leaf extracts of C. roseus on plasma lipidprofil levels in rats cholesterol rich diet and atherogenic index. This study was carried out on 15 SpraqueDawley male rats randomly distributed into five groups (n=3). Rats hypercholesterolemic wereadministrated cholesterol rich diet containing 1% (w/w). Normal control group with normal diet whitoutextracts (K1), positive control hypercholesterolemic group (K2) with cholesterol rich diet whitout extracts,and others three groups (K3-K5) were feed high cholesterol and 1 mL of aqueous leaf extracts of C. roseuswith a dose of 20% (w/v), 40% (w/v) and 80% (w/v) respectively, administered twice daily 1 mL orally.Treatment was given for 28 days. After treatment, the plasma lipids profile such cholesterol total, highdensity lipoprotein (HDL), low density lipoprotein (LDL), triglyceride (TGA) level were measured. Theresults showed that during the period of treatment with cholesterol rich diet have produced under condition hypercholesterolemic of rats with average cholesterol levels of 124.33 ± 4.04 mg/dL (K2 group). Treatmentwith extract dose of 80% showed the best results among the other doses in reducing levels of total cholesterol,triglycerides, LDL and raise HDL levels. Extract treatment dose of 80% up to four weeks resulted incholesterol total (79.33±3.51 mg/dL), TGA (72.33±6.65 mg/dL), HDL (55.00±3.60 mg/dL), and LDL(9.87±5.34mg/dL). In addition, value ratio of cholesterol:HDL was 1.4: 1 and atherogenic index value was0.44. These results suggest that extracts of leaf C. roseus optimum doses 80% (w/v) has hipolipidemicactivity in hypercholesterolemic rats and it has low atherogenic index value.

Grape Seed Proanthocyanidins Attenuate Anxiety-Like Behavior in an Experimental Model of Dietary-Induced Hypercholesterolemia in Rats.

Grape seed proanthocyanidins have many health-protective effects. The present work aimed to assess their possible anxiolytic effects in dietary-induced hypercholesterolemia in rats. 30 Male Wistar rats were divided into 3 groups (n = 10): control (normal chow), high cholesterol (cholesterol and cholic acid chow) and high cholesterol + grape seed extract (hypercholesterolemic chow + grape seed extract, 100 mg/kg body weight/day). After 4 months, total cholesterol levels and animals' behavior in the open field and elevated plus maze were assessed. High-cholesterol diet elevated cholesterol levels (p < 0.001 vs control group), however, grape seed administration ameliorated this elevation (p < 0.001 vs high-cholesterol untreated group). In the open field, hypercholesterolemic rats showed increased periods of immobility (138 ± 20.3 seconds (s) vs 96.9 ± 14.5 in control rats p < 0.001) and time latency to enter field center (109 ± 18.3 s compared to 40.8 ± 10.5 s in the control group p < 0.001). Both parameters were reduced by grape seed treatment (p < 0.01, p < 0.001 vs the untreated hypercholesterolemic group, respectively). Elevated plus maze testing demonstrated higher closed-arm entries (5.5 ± 1.1 in hypercholesterolemic animals vs 3 ± 1.1 in the control group p < 0.001) and lower percentage of time spent in open arms (19.7 ± 3.5 % vs 35.8 ± 4.8 % in control rats p < 0.001). Grape seed extract significantly enhanced the percentage of time spent in open arms (p < 0.001 compared to hypercholesterolemic rats). The present results highlight the possible anxiolytic effect of grape seed proanthocyanidins in dietary-induced hypercholesterolemia.

Hypercholesterolemia and Ecto-enzymes of Purinergic System: Effects of Paullinia cupana.

Hypercholesterolemia is a metabolic disorder characterized by high levels of low-density lipoprotein and blood cholesterol, causing inflammatory lesion. Purinergic signaling modulates the inflammatory and immune responses through adenine nucleotides and nucleoside. Guaraná has hypocholesterolemic and antiinflammatory properties. Considering that there are few studies demonstrating the effects of guaraná powder on the metabolism of adenine nucleotides, we investigated its effects on the activity of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase activity in lymphocytes of rats with diet-induced hypercholesterolemia. The rats were divided into hypercholesterolemic and normal diet groups. Each group was subdivided by treatment: saline, guaraná powder 12.5, 25, or 50 mg/kg/day and caffeine concentration equivalent to highest dose of guaraná, fed orally for 30 days. An increase in adenosine triphosphate hydrolysis was observed in the lymphocytes of rats with hypercholesterolemia and treated with 25 or 50 mg/kg/day when compared with the other groups. The hypercholesterolemic group treated with the highest concentration of guaraná powder showed decreased ecto-adenosine deaminase activity compared with the normal diet groups. Guaraná was able to reduce the total cholesterol and low-density lipoprotein cholesterol to basal levels in hypercholesterolemic rats. High concentrations of guaraná associated with a hypercholesterolemic diet are likely to have contributed to the reduction of the inflammatory process.

Pharmacological preconditioning and postconditioning with nicorandil attenuates ischemia/reperfusion-induced myocardial necrosis and apoptosis in hypercholesterolemic rats.

Pharmacological preconditioning and postconditioning may reduce myocardial necrosis and apoptosis during ischemia/reperfusion (I/R), however, hypercholesterolemia interferes with the associated cardioprotective mechanisms. The present study investigated whether pharmacological preconditioning and postconditioning with nicorandil could attenuate myocardial necrosis and apoptosis induced by I/R in hypercholesterolemic rats, and explored the possible mechanisms involved. Male Wistar rats (n=160) were fed normal (normocholesterolemic group, n=10) or high-cholesterol (hypercholesterolemic group, n=150) diets for 8 weeks. Hearts harvested from the normal and hypercholesterolemic rats were subsequently placed on modified Langendorff perfusion apparatus and 30-min global ischemia was performed, followed by 120-min reperfusion. Nicorandil (1, 3, 10, 30, 100 µmol/l), and mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel blocker 5-hydroxydecanoic acid sodium salt (5-HD) (100 µmol/l) or soluble guanylyl cyclase (sGC) blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µmol/l) were perfused for 10 min, prior to ischemia or at the onset of reperfusion. The myocardial infarct size was determined by triphenyltetrazolium chloride staining, and cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In order to investigate the potential mechanisms, the expression levels of caspase-3, B-cell lymphoma-2 (Bcl-2) proteins and Bcl-2-associated X protein (Bax) were measured using western blot analysis. The present study demonstrated that, in hypercholesterolemic rats, pharmacological preconditioning and postconditioning with nicorandil decreased I/R-induced myocardial necrosis and apoptosis in a concentration-dependent manner. The optimal preconditioning and postconditioning concentration of nicorandil determined to have anti-infarct and anti-apoptosis effects was 30 µmol/l, which significantly (P<0.05) reduced the infarct size to 14.88±3.25% and 15.96±3.29%, and attenuated the percentage of cardiomyocyte apoptosis to 25.20±3.93% and 26.18±4.82%, respectively, compared with the I/R group. However, the cardioprotective effects of nicorandil were partially suppressed by cotreatment with 5-HD or ODQ. Western blot analysis demonstrated that pharmacological preconditioning and postconditioning with nicorandil significantly downregulated caspase-3 and Bax expression, and upregulated Bcl-2 expression compared with the I/R group (P<0.05). The results of the present study suggest that pharmacological preconditioning and postconditioning with nicorandil may protect hypercholesterolemic hearts against I/R-induced necrosis and apoptosis; and the cardioprotective effects of nicorandil may be due to the dual pharmacological mechanisms of opening the mitoKATP channels and a nitric oxide/sGC-dependent mechanism, and regulation of the expression of caspase-3, Bax and Bcl-2.

Pitavastatin calcium improves endothelial function and delays the progress of atherosclerosis in patients with hypercholesterolemia.

Statins have proven efficacy in inhibiting the onset and progress of atherosclerosis. The effectiveness of pitavastatin in reversing carotid atherosclerosis associated with hypercholesterolemia (HC) is unknown. To explore the simultaneous effects of pitavastatin calcium on brachial arterial flow-mediated vasodilatation (FMD), carotid intima-media thickness (IMT), and arterial stiffness (β), three surrogate markers of atherosclerosis were studied in HC patients. A randomized, double-blind trial was performed with 40 HC subjects who fulfilled the inclusion/exclusion criteria. Patients were given pitavastatin calcium 1 mg/d (Group 1) or 2 mg/d (Group 2) for 8 weeks. There were 20 patients in each group, and 30 gender- and age-matched healthy subjects as controls were recruited. FMD of the brachial artery, carotid IMT, and arterial stiffness indicated by β were measured at baseline and at 8 weeks after starting pitavastatin calcium therapy using ultrasound techniques. Biochemical tests were also made on all subjects. At baseline, higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), reduced FMD, and increased β and IMT were observed in HC patients (P<0.001 for all) compared with controls. After 8 weeks, TC was decreased by 20.59%/27.56% and LDL-C 30.92%/35.64%, respectively, in comparison to baseline groups; the HC groups had reduced β and improved endothelial function over the 8-week follow-up (P<0.05-0.001); nonetheless, no significant alterations of IMT were found (P>0.05). Significant negative interactions between TC/LDL and FMD (P<0.05-0.001), positive interactions between TC and IMT (P=0.003) and between TC/LDL and β (P<0.001-0.000) were found. Treatment with pitavastatin calcium exerted favorable effects on endothelial function and arterial stiffness. It also improved carotid atherosclerosis in patients with HC.

Primary hyperlipidemia in children: clinical, biochemistry characteristics and outcome

Patients and methods From 2007 to 2013, 30 children with primary hyperlipidemia were recruited and were treated with diet and/or lipid-lowering drug therapy at the National Hospital of Pediatrics, Hanoi, Vietnam. Clinical symptoms and biochemical finding, outcome of treatment were studied. Results: Among 30 cases from 28 families, 8 patients were mixed hyperlipidemia (MHL), 13 patients were hypertriglyceridemia (HT) and 9 patients were hypercholesterolemia (HC). Mean age of diagnosis was 5.5 years (1 month – 16 years). The rate of male/female was 13/17. Clinical manifestations included hepatomegaly (4 cases), xanthemas in the knees and elbows (5 cases), “creamy” blood (21 cases). Twenty cases were clinical asymptomatic. 8/28 patients had family history with hyperlipidemia and cardiovascular diseases. Serum cholesterol levels of HC group was 9.2 ± 4 mmol/l. Serum triglyceride level of HT group was 23.6 ± 9.9 mmol/l. MHL group had hypercholesterolemia (12.1 ± 4.5 mmol/l) and hypertriglyceridemia (20.3 ± 10.5 mmol/l). After interventions, HT group had the best outcome with serum triglyceride level was 10.1 ± 4.6 mmol/l, next to MHL group with serum cholesterole level was 5.8 ± 1.8 mmol/l, and serum triglyceride level was 9.5 ± 5.2 mmol/l; finally, serum cholesterole level of HC group was 12.4 ± 5.5 mmol/l. Five infants with HT had the best outcome of treatment: serum triglyceride level decreased from 19 57.6 mmol/l to 5 10 mmol/l. Two patients with HC had the worsen results (unchanged blood lipid level).

Comparative study of cholinergic and oxidative stress biomarkers in brains of diabetic and hypercholesterolemic rats

Diabetes mellitus (DM) and hypercholesterolemia (HC) when poorly controlled lead to debilitating central nervous system complications including cognitive deficits and memory impairment. In the present study, we investigated the mechanisms that may be responsible for such deficits. Both diabetes and HC were induced in two groups of rats independently using alloxan and high cholesterol diet, respectively. Acetyl cholinesterase was significantly increased in brain of diabetic rats. Also, brain malondialdehyde level was extremely elevated in both diabetic and hypercholesterolemic groups. Meanwhile, brain albumin was markedly decreased in both of them. However, the brain iron level was significantly increased in DM with concomitant increase in total antioxidant capacity in the same group as compared to the normal control. The concentration of brain calcium was noticeably increased in HC group. Our results were confirmed by the increased activity of lactate dehydrogenase in both DM and HC groups, indicating major brain cytotoxicity. Overall, our results suggested that both DM and HC have deleterious effects on the brain which may be attributed to oxidative stress and dysregulation of both cholinergic function and calcium level. Administration of antioxidant is recommended in both cases.