Excess Low Density Lipoprotein Research Articles

Aptamer and sodium alginate decorated graphene oxide composite material with ion responsiveness for Low-density lipoprotein trapping

The accumulation of excess Low-density lipoprotein (LDL) is strongly associated with the occurrence of heart failure, coronary artery disease and hypercholesterolaemia, and is a major factor in cardiovascular and cerebrovascular disease. Concerns about the ways to decrease LDL level have continuously arisen. In this study, an ionic stimulation-responsive composite (i.e., GO@Apt@SA) is prepared with modification of graphene oxide (GO) utilising LDL-aptamer (Apt) and sodium alginate (SA). The ion-responsive behaviour of GO@Apt@SA synergistically interacts with the specific recognition property of the aptamer, enabling adsorption of LDL with higher capacity and specificity. Under the optimal experimental conditions, the maximum adsorption capacity of GO@Apt@SA for LDL is 730.6 μg mg−1. Interestingly, the aptamer complementary chain could trigger the release of LDL with favourable elution efficiency, which competitively binds with LDL-specific aptamer to trigger LDL release. More importantly, GO@Apt@SA exhibits satisfactory adsorption performances for LDL in goat serum, meaning that the composite material and technology are available for the extraction of LDL from complex sample matrices.

Tetrahydroberberine alleviates high-fat diet-induced hyperlipidemia in mice via augmenting lipoprotein assembly-induced clearance of low-density lipoprotein and intermediate-density lipoprotein

The promotion of excess low-density lipoprotein (LDL) clearance stands as an effective clinical approach for treating hyperlipidemia. Tetrahydroberberine, a metabolite of berberine, exhibits superior bioavailability compared to berberine and demonstrates a pronounced hypolipidemic effect. Despite these characteristics, the impact of tetrahydroberberine on improving excessive LDL clearance in hyperlipidemia has remained unexplored. Thus, this study investigates the potential effects of tetrahydroberberine on high-fat diet-induced hyperlipidemia in mice. The findings reveal that tetrahydroberberine exerts a more potent lipid-lowering effect than berberine, particularly concerning LDL-cholesterol in hyperlipidemic mice. Notably, tetrahydroberberine significantly reduces serum levels of upstream lipoproteins, including intermediate-density lipoprotein (IDL) and very low-density lipoprotein, by promoting their conversion to LDL. This reduction is further facilitated by the upregulation of hepatic LDL receptor expression induced by tetrahydroberberine. Intriguingly, tetrahydroberberine enhances the apolipoprotein E (ApoE)/apolipoprotein B100 (ApoB100) ratio, influencing lipoprotein assembly in the serum. This effect is achieved through the activation of the efflux of ApoE-containing cholesterol in the liver. The ApoE/ApoB100 ratio exhibits a robust negative correlation with serum levels of LDL and IDL, indicating its potential as a diagnostic indicator for hyperlipidemia. Moreover, tetrahydroberberine enhances hepatic lipid clearance without inducing lipid accumulation in the liver and alleviates existing liver lipid content. Importantly, no apparent hepatorenal toxicity is observed following tetrahydroberberine treatment for hyperlipidemia. In summary, tetrahydroberberine demonstrates a positive impact against hyperlipidemia by modulating lipoprotein assembly-induced clearance of LDL and IDL. The ApoE/ApoB100 ratio emerges as a promising diagnostic indicator for hyperlipidemia, showcasing the potential clinical significance of tetrahydroberberine in lipid management.

Lipoproteins and Their Effects on the Cardiovascular System.

Coronary heart disease is the foremost leading cause of death across the world. It mainly involves the blood vessels, which supply the heart. Plaque formation due to lipid deposition leads to the narrowing of the vessels, obstructing blood flow. Therefore, lipoproteins such as high-density lipoproteins (HDL), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and chylomicrons play a crucial role in cardiovascular diseases. Lipoproteins are carrier molecules made up of proteins and fats. They carry cholesterol through the bloodstream and transport it to the peripheral tissues or the liver. There are several classes of lipoproteins in the blood, namely HDL, LDL, VLDL, and chylomicrons. Depending on the lipoproteins, an excess of them can either harm or benefit the body. Low-density lipoprotein, nicknamed 'the bad cholesterol,' transports fatty molecules from the liver and deposits them in peripheral tissues or central vessels. Thus, excess LDL can cause blockage of the arteries supplying major organs. High-density lipoprotein, nicknamed 'the good cholesterol,' transports the excess fatty molecules to the liver for their metabolism and removal from the body. Hence, high levels of HDL are an indication of a healthy body. Thus, lipoproteins are important molecules, and their proper regulation is essential to maintaining a healthy body. An effective way to maintain a balanced lipoprotein level is to have a properly balanced diet with high protein and low fat. Regular exercise, both indoors and outdoors, is recommended. If cholesterol levels are not maintained by diet and exercise, medication is advised after consulting medical experts. This review aims to inform people about lipoproteins, their importance, and maintaining a healthy lipoprotein level.

Proteomic analysis reveals the mechanisms of the astaxanthin suppressed foam cell formation

AimsLipid metabolism in macrophages plays a key role in atherosclerosis development. Excessive low-density lipoprotein taken by macrophages leads to foam cell formation. In this study, we aimed to investigate the effect of astaxanthin on foam cells, and using mass spectrometry-based proteomic approaches to identified the protein expression changes of foam cells. Main methodsThe foam cell model was build, then treated with astaxanthin, and tested the content of TC and FC. And proteomics analysis was used in macrophage, macrophage-derived foam cells and macrophage-derived foam cells treated with AST. Then bioinformatic analyses were performed to annotate the functions and associated pathways of the differential proteins. Finally, western blot analysis further confirmed the differential expression of these proteins. Key findingsTotal cholesterol (TC) while free cholesterol (FC) increased in foam cells treated with astaxanthin. The proteomics data set presents a global view of the critical pathways involved in lipid metabolism included PI3K/CDC42 and PI3K/RAC1/TGF-β1 pathways. These pathways significantly increased cholesterol efflux from foam cells and further improved foam cell-induced inflammation.Significance: The present finding provide new insights into the mechanism of astaxanthin regulate lipid metabolism in macrophage foam cells.

Study Protocol: Effects of Daily Prune Consumption on Lipid Profile, Inflammation, and Oxidative Stress

ObjectivesCardiovascular disease (CVD) is the leading cause of death and disability worldwide. Atherosclerosis is recognized as a primary underlying cause of CVD resulting from oxidative stress, chronic inflammation, and excess low-density lipoprotein cholesterol (LDL). Prunes (Prunus domestica L.) are a nutritious food with components associated with improved cardiovascular health, including soluble fiber and polyphenolic compounds. The objective of this study is to investigate the cardioprotective benefits of prunes and determine the extent to which daily prune consumption effects blood lipids, oxidative stress, and chronic inflammation in men.MethodsHealthy osteopenic men aged 55 to 80 years old with body mass index of <18 to >40 data were included in this 12-month, parallel design, randomized controlled trial. Participants were placed into one of three treatment groups: 50 g/day prune, 100 g/day prune, or control (multivitamin only) for 12 months. All groups consumed a multivitamin containing 450 mg calcium and 800 IU vitamin D. During each visit (baseline, 3, 6, and 12 months) height, body weight, waist and hip circumference, heart rate, and blood pressure were assessed. Fasting blood and urine samples were collected at each time point, and participants completed a 3-day food record and validated physical activity questionnaire. Blood total cholesterol (TC), LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C) and biomarkers of inflammation and oxidative stress including high-sensitivity C-reactive protein (hsCRP), Tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), lipid peroxidation (LPO), and total antioxidant capacity (TAC) will be measured.ResultsStudy recruitment and retention is complete. Data analysis has yet to begin.ConclusionsBased on the literature, whole foods high in polyphenols and soluble fiber, such as prunes, are beneficial in reducing chronic inflammation and circulating LDL-C. In the current study, we expect that long-term daily consumption of prunes will improve CVD risk factors including reductions in LDL and TC and provide antioxidant and anti-inflammatory cardiovascular benefits in older men. Findings from this research will further our understanding of the role that prunes may have in improving cardiovascular health.Funding SourcesUSDA, California Prune Board, and Shaklee.

Gypenoside LVI improves hepatic LDL uptake by decreasing PCSK9 and upregulating LDLR expression

BackgroundsAtherosclerotic Cardiovascular Disease (ASCVD) is defined as ischemic or endothelial dysfunction-various inflammatory diseases, which is mainly caused by excessive low-density lipoprotein cholesterol (LDL-C) in circulating blood. Gynostemma pentaphyllum is a traditional Chinese medicine, and total Gypenosides are used for the treatment of hyperlipidemia and to reduce circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) level. However, which gypenoside involved in the modulation of PCSK9 expression is still unknown. PurposeThis study aimed to discover effective PCSK9 inhibitors from Gypenosides in accordance with the 2019 ESC/EAS guidelines. MethodsHPLC was employed to determine major six components of Gypenosides. The inhibitory activity on secreted PCSK9 in HepG2 of six major compounds from Gypenosides were screened by ELISA. The level of low-density lipoprotein (LDL) receptor (LDLR) was determined by Flow cytometry and Immunofluorescence. The expression levels of PCSK9, LDLR and Sterol-regulatory element binding proteins-2 (SREBP-2) were analyzed by qPCR and Western blot. DiI-LDL was added to evaluated LDL uptake into HepG2. ResultsThe results suggested that the mRNA and protein levels of PCSK9 were down-regulated by Gypenoside LVI and the LDLR degradation in lysosomes system was inhibited, thereby leading to an increasing in LDL uptake into HepG2 cells. Furthermore, Gypenoside LVI decreased PCSK9 expression induced by stains. Altogether, Gypenoside LVI enhances LDL uptake into HepG2 cells by increased LDLR level on cell-surface and suppressed PCSK9 expression. ConclusionThis indicates that Gypenoside LVI can be used as a useful supplement for statins in the treatment of hypercholesterolemia. This is firstly reported that monomeric compound of G. pentaphyllum planted in Hunan province has the effect of increasing LDL-C uptake in hepatocytes via inhibiting PCSK9 expression.

Selective Molecular Recognition of Low Density Lipoprotein Based on β-Cyclodextrin Coated Electrochemical Biosensor.

The excess of low-density lipoprotein (LDL) strongly promotes the accumulation of cholesterol on the arterial wall, which can easily lead to the atherosclerotic cardiovascular diseases (ACDs). It is a challenge on how to recognize and quantify the LDL with a simple and sensitive analytical technology. Herein, β-cyclodextrins (β-CDs), acting as molecular receptors, can bind with LDL to form stable inclusion complexes via the multiple interactions, including electrostatic, van der Waals forces, hydrogen bonding and hydrophobic interactions. With the combination of gold nanoparticles (Au NPs) and β-CDs, we developed an electrochemical sensor providing an excellent molecular recognition and sensing performance towards LDL detection. The LDL dynamic adsorption behavior on the surface of the β-CD-Au electrode was explored by electrochemical impedance spectroscopy (EIS), displaying that the electron-transfer resistance (Ret) values were proportional to the LDL (positively charged apolipoprotein B-100) concentrations. The β-CD-Au modified sensor exhibited a high selectivity and sensitivity (978 kΩ·µM−1) toward LDL, especially in ultra-low concentrations compared with the common interferers HDL and HSA. Due to its excellent molecular recognition performance, β-CD-Au can be used as a sensing material to monitor LDL in human blood for preventing ACDs in the future.

A New Insight into Pathogenesis of Cardiovascular Diseases: Stress Induced Lipid Mediated, Vascular Diseases

Based on my clinical experience and knowledge gained through extensive research in this area, I have come up with a hypothesis which sheds more light in the pathogenesis of cardiovascular diseases. Atherosclerosis is implicated as playing the key role in the pathogenesis of cardiovascular diseases which involves large and medium sized arteries. There is now evidence that atherosclerosis is an immuno-inflammatory process. My hypothesis is that chronic psychosocial stress is the main trigger for the systemic inflammation which results by activation of Hypothalamus-Pituitary-Adrenal (HPA) axis and Sympathetic-Adrenal-Medulla (SAM) axis. This stress response sets into motion innate immune response, initiating a cascade of events which include: Release of neuro-endocrine transmitters, endothelial dysfunction, and increased permeability of micro vascular circulation and increased delivery of free fatty acids in circulation among others. Liver responds by increased Low Density Lipoproteins (LDL) production which continuously enters the arteries, excess LDL is transformed into oxidized low density lipoproteins (ox LDL). ox LDL goes through pattern recognition and is recognized as antigen. Adaptive immunity is activated. ox LDL is pro oxidant, results in inflammation, reactive oxygen species are released causing oxidative stress. This causes atherosclerosis in large and medium sized arteries and tissue damage in organs sub served by micro vasculature. Hence the process being systemic inflammation is not limited to large and medium sized arteries but is global in reach involving the entire vasculature. The pathogenesis of these disorders may be classified as “stress induced, lipid mediated vascular inflammation. This article will review stress and pathophysiology of stress, pathophysiology of cardiovascular diseases which includes endothelial dysfunction, pathogenesis of atherosclerosis, inflammation in atherosclerosis, and current concepts of diseases comprising cardiovascular diseases, including the risk factors for CVDs. It enters the stage of hypothesis based on the knowledge gained. It discusses microcirculation, and goes over disorders involving microcirculation. Oxidative Stress is reviewed followed by a brief summary. It winds up with discussion, management and conclusion.

Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor.

Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus-mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis.

Two Neglected Biologic Risk Factors in Bone Grafting and Implantology: High Low-Density Lipoprotein Cholesterol and Low Serum Vitamin D

Following a failure of a bone graft or an implant placement, the hypothesis of a biological abnormality is rarely considered as a possible cause. A systematic search of peer-reviewed literature for dyslipidemia or vitamin D deficiency may explain this lack of consideration. Excess low-density lipoprotein cholesterol (dyslipidemia) is responsible for a slower bone metabolism or lower dental implant osseointegration. In addition, vitamin D is a key factor for linking innate and adaptive immunity. Both of these factors are compromised under the conditions of vitamin D deficiency. Therefore, vitamin D deficiency slows implant osseointegration and increases the risk of graft infection. Vitamin D is also involved in immune function and therefore allergic reactions.

LDL‐cholesterol versus HDL‐cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos

Atherosclerosis is a complex disease in which many processes contribute to lesion development. Yet, it is well accepted that high serum levels of low-density lipoproteins (LDL) play a main role in the initiation and progression of atherosclerosis. Despite currently available optimal LDL-lowering therapies, a worrisome number of clinical events still occur. The protective effect of high-density lipoproteins (HDL) in atherosclerosis, either by suppressing vascular-LDL accumulation, inflammation, oxidation, endothelial damage, and thrombosis, has supported the need of the use of HDL-raising therapies to address this residual risk. Results obtained in some studies, however, have shown that HDL quality, rather than quantity, should be the target of future pharmacological therapies. Here, we will first explore the mechanism by which excess LDL is fundamental in the development of atherosclerosis and its thrombotic complications, behaving as a factor that introduces chaos in the vascular wall. Afterwards, we will explore how functional HDL, through various cellular and molecular mechanisms, facilitates the resolution of this vascular chaos by suppression of atherosclerosis progression and induction of regression.

Impact of laparoscopic sleeve gastrectomy on body mass index, ghrelin, insulin and lipid levels in 100 obese patients

IntroductionA high percentage of patients benefit from bariatric procedures in terms of metabolic effect and substantial body mass reduction. These procedures improve glucose metabolism leading to the amelioration or complete resolution of type 2 diabetes, reduction of insulin resistance and alleviation of metabolic syndrome effects.AimTo assess the impact of laparoscopic sleeve gastrectomy (LSG) on the plasma levels of ghrelin, insulin, glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions as well as aspartate and alanine transaminases in patients with obesity.Material and methodsOne hundred patients who underwent laparoscopic sleeve gastrectomy in our centre between 2005 and 2009 were included in the study. Among them were 48 males with an average age of 47.93 ±9.24 years and 52 females with an average age of 44.19 ±9.33 years. Percentage excess weight loss (%EWL), percentage excess body mass index (BMI) loss (%EBL), ghrelin, insulin, glucose, triglycerides, cholesterol, HDL, LDL, alanine transferase (ALT), and asparagine transferase (AST) were measured preoperatively and on the 7th day then 1, 3 and 6 months after the surgery.ResultsStatistically significant reduction in postoperative BMI, plasma levels of glucose and insulin as well as the homeostatic model assessment insulin resistance (HOMA IR) score was noted in comparison to the preoperative values. The ghrelin levels decreased. Lipid profile, AST and ALT levels varied depending on the particular time points.ConclusionsLaparoscopic sleeve gastrectomy reduces body mass and leads to the decrease of concentration of ghrelin in plasma as well as to the improvement of metabolism of insulin, glucose, cholesterol and triglycerides. The above changes alleviated symptoms of metabolic syndrome and obesity related co-morbidities.

Nanoparticles: A Promising Therapeutic Approach in Atherosclerosis

Coronary atherosclerosis is the largest cause of mortality and morbidity in industrialised countries. Despite recent advances in medical therapies, the prevention and treatment of atherosclerosis remain suboptimal. Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall, involving the accumulation of macrophages and excess low density lipoproteins (LDL), the formation of foam cells which create the atheromatous plaque, resulting in stenosis, aneurysm and plaque rupture leading to acute coronary events. Every step in the atherogenesis process is a potential therapeutic target for both the prevention and regression of atherosclerosis. A novel approach is the use of nanoparticles containing drugs, providing new perspectives in targeted modification of these pathways. Nanoparticles are ultrafine particles sized between 1-100 nm. By using specific methods, nanoparticles can be filled with drugs and achieve targeted drug delivery near the diseased area. In this review article we describe the basic actions of nanoparticles, and we discuss their potential applications in atherosclerosis. We also discuss their advantages and we expose the existing toxicity issues, making it clear however, that the use of nanoparticles is one of the most promising therapeutic strategies against atherosclerosis.

Binding of liver derived, low density hepatitis C virus to human hepatoma cells

HCV recovered from low density fractions of infected blood is associated with lipid and host apo-lipoproteins in lipo-viro-particles (LVP). It has been proposed that these particles are capable of binding and entering hepatocytes by viral glycoprotein independent mechanisms utilizing uptake pathways of normal host lipoproteins after binding to cell surface glycosaminoglycans (GAG), the low density lipoprotein receptor (LDL-r) or scavenger receptor B1 (SR-B1). In this study binding to human hepatoma cells of HCV low density RNA containing particles, semi-purified from macerates of infected human liver, is compared with that of normal host low density lipoprotein (LDL). Binding of both LDL and HCV low density RNA containing particles paralleled LDL-r but not SR-B1 expression on the recipient cells. Binding of both particle types was sensitive to suramin at 0 degrees C but less so at 37 degrees C suggesting that they both bind initially to GAG but, at 37 degrees C, are internalized or transferred to a suramin resistant receptor. Suramin resistant uptake of both particles was blocked in the presence of excess LDL or oxidized LDL. However, whilst LDL uptake was blocked by anti-apoB-100, HCV low density RNA uptake was enhanced by anti-apoB100 and further enhanced by a cocktail of anti-apo-B100 and anti-apoE. Pre-incubation of HCV low density RNA containing particles with antibodies to the E2 glycoprotein had little or no effect on uptake. These data indicate that whilst liver derived HCV RNA containing particles are taken up by HepG2 cells by a virus glycoprotein independent mechanism, the mechanism differs from that of LDL uptake.

Oxidation of chylomicron remnant-like particles inhibits their uptake by THP-1 macrophages by apolipoprotein E-dependent processes

The influence of the oxidative state of chylomicron remnants (CMR) on the mechanisms of their uptake and induction of lipid accumulation by macrophages derived from the human monocyte cell line, THP-1, during foam cell formation was investigated using chylomicron-remnant-like particles (CRLPs) at 3 different levels of oxidation. The oxidative state of CRLPs was varied by exposure to CuSO4 (oxCRLPs) or incorporation of the antioxidant, probucol (pCRLPs) into the particles. oxCRLPs caused significantly less accumulation of triacylglycerol in the macrophages than CRLPs, and their rate of uptake was lower, while pCRLPs caused more lipid accumulation and were taken up faster. Uptake of all 3 types of particles was inhibited to a similar extent when entry via the low density lipoprotein (LDL) receptor related protein (80–90%), LDL receptor (−30–40%), CD36 (−40%) and phagocytosis (−35–40%) was blocked using lactoferrin, excess LDL, anti-CD36 and cytochalasin D, respectively, but blocking scavenger receptors-A or -B1 using poly inosinic acid or excess HDL had no effect. These findings show that oxidation of CRLPs lowers their rate of uptake and induction of lipid accumulation in macrophages. However, oxidation does not change the main pathways of internalisation of CRLPs into THP-1 macrophages, which occur mainly via the LRP with some contribution from the LDLr, while CD36 and phagocytosis have only a minor role, regardless of the oxidative state of the particles. Thus, the effects of CMR oxidation on foam cell formation contrast sharply with those of LDL oxidation and this may be important in the role of dietary oxidized lipids and antioxidants in modulating atherosclerosis.

Incorporation of lycopene into chylomicron remnant-like particles inhibits their uptake by HepG2 cells

The influence of the incorporation of the antioxidant tomato pigment, lycopene, into chylomicron remnant-like particles (CRLPs) on their uptake by the liver cells was investigated. CRLPs or CRLPs containing lycopene (lycCRLPs) radiolabelled with [ 3H]triacylglycerol were incubated with cells of the human liver hepatoma cell line, HepG2, and the radioactivity taken up by the cells was determined. LycCRLPs were taken up significantly more slowly than CRLPs over a concentration range of 5–60 μg cholesterol/ml and a time course of 2–6 h. Pre-incubation of the hepatocytes with an excess of low density lipoprotein (LDL) inhibited the uptake of CRLPs by about 50%, but had no effect on the uptake of lycCRLPs, and under these conditions the CRLPs and lycCRLPs were taken up at similar rates. In HepG2 cells pre-treated with suramin, which inhibits uptake via the LDL receptor-related protein (LRP), the uptake of CRLPs was also inhibited (− 37%) to a greater extent than that of lycCRLPs (− 24%), so that the values for the two types of particle were no longer significantly different. Heparinase increased the uptake of lycCRLPs (about 2 fold), but not CRLPs, bringing it to a level equivalent to that seen with the control particles. These findings demonstrate that the incorporation of lycopene into CRLPs decreases their uptake by HepG2 cells and suggest that this effect is due to differential interaction with the LDL receptor and the LRP-receptor-mediated pathways, and may also involve binding of the particles to HSPG.

HMG-CoA Reductase Inhibitors in Chronic Heart Failure

HMG-CoA reductase inhibitors (statins) have been shown to reduce mortality and cardiovascular morbidity in patients with hyperlipidaemia and those with coronary artery disease. However, evidence for statin treatment in patients with chronic heart failure (CHF) remains a subject of debate. Patients with heart failure were generally excluded in the existing trials and a different patient population with a distinct pattern of morbidity and treatment was studied. In addition, no safety data are available for statins in patients with heart failure, where there are potential concerns about coenzyme Q10 depletion and excessive low-density lipoprotein reduction. This review summarises the clinical and preclinical evidence for potential beneficial effects of statins in CHF. In experimental systems, statins have been shown to improve cardiac function through antioxidative and anti-inflammatory action. Statins improve endothelial function, may reduce neurohormonal activation, and stimulate endothelial progenitor cells. Some of these effects occur independently of cholesterol lowering and can be explained by inhibition of isoprenylation of signal transducing proteins of the family of Rho guanosine triphosphatases. Two ongoing controlled randomised trials (CORONA [Controlled Rosuvastatin Multinational Study in Heart Failure] and GISSI-HF [Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico--Heart Failure]) will help us to assess whether the described beneficial effects of statins in heart failure outweigh the potential negative effects and translate into the reduction of clinical endpoints.

Regulation of lipoprotein trafficking in the kidney: role of inflammatory mediators and transcription factors.

Inflammation and dyslipidaemia both play important roles in the development of glomerular atherosclerosis in renal diseases. We have demonstrated that inflammatory mediators induced Scr (scavenger receptor) expression and the formation of foam cells, and that AP-1 (activator protein 1)/ets were necessary transcriptional factors for Scr induction in HMCs (human kidney mesangial cells). Most cells are protected from excessive native LDL (low-density lipoprotein) accumulation by tight feedback regulation of the LDLr (LDL receptor). However, we observed that HMCs formed foam cells via the LDLr pathway when incubated with IL-1beta (interleukin-1beta; 5 ng/ml) and unmodified LDL (200 microg/ml), suggesting that inflammatory mediators may disrupt the cholesterol-mediated feedback regulation. This feedback involves cholesterol-mediated down-regulation of LDLr controlled by SCAP [SREBP (sterol responsive element-binding protein) cleavage-activating protein]. We have also demonstrated that both tumour necrosis factor alpha and IL-1beta increased nuclear SREBP-1 levels by increasing SCAP mRNA expression, even in the presence of a high concentration of LDL. Since intracellular lipid content is governed by both influx and efflux mechanisms, we set out to examine the impact of inflammatory cytokines on cholesterol efflux, a process mediated by the protein ABCA1 (ATP binding cassette A1). IL-1beta inhibited [(3)H]cholesterol efflux from HMCs by inhibition of the peroxisome-proliferator-activated receptor/LXR (liver X receptor)/ABCA1 pathway. Taken together, our results suggest that inflammatory mediators increase lipid accumulation in HMCs not only by promoting increased lipoprotein uptake by Scr and LDLr, but also by inhibiting ABCA1-mediated cholesterol efflux to high-density lipoprotein.

A phenomenological model for atherosclerotic plaque growth and rupture

The objective of this communication is to develop a computer-based framework for the overall coupled phenomena leading to growth and rupture of atherosclerotic plaques. The modeling is purposely simplified to expose the dominant phenomenological controlling mechanisms, and their coupled interaction. The main ingredients of the present simplified modeling approach, describing the events that occur due to the presence and oxidation of excess low-density lipoprotein (LDL) in the intima, are: (i) adhesion of monocytes to the endothelial surface, which is controlled by the intensity of the blood flow and the adhesion molecules stimulated by the excess LDL, (ii) penetration of the monocytes into the intima and subsequent inflammation of the tissue, and (iii) rupture of the plaque accompanied with some degree of thrombus formation or even subsequent occlusive thrombosis. The set of resulting coupled equations, each modeling entirely different physical events, is solved using an iterative staggering scheme, which allows the equations to be solved in a computationally convenient decoupled fashion. Theoretical convergence properties of the scheme are given as a function of physical parameters involved. A numerical example is given to illustrate the modeling approach and an a priori prediction for time to rupture as a function of arterial geometry, diameter of the monocyte, adhesion stress, bulk modulus of the ruptured wall material, blood viscosity, flow rate and mass density of the monocytes.

The fatty acid composition of chylomicron remnants influences their binding and internalization by isolated hepatocytes.

The binding and internalization of (125)I-labelled chylomicron remnants derived from palm, olive, corn, or fish oil (rich in saturated, monounsaturated, n-6, or n-3 polyunsaturated fatty acids, respectively) by hepatocytes from rats fed a low-fat diet or a diet supplemented with the corresponding fat for 21 days was investigated. In hepatocytes from rats fed the low-fat diet, the association of radioactivity with the cells at 4 degrees C (a measure of initial binding only) was similar with all types of remnants tested, but was more rapid at 37 degrees C (a measure of binding plus internalization) when fish oil, as compared to olive, corn or palm oil remnants, was used, and similar differences in the internalization of the particles were observed. In contrast, when hepatocytes from rats fed the fat-supplemented diets were used, the rate of association at 37 degrees C of remnants with cells from rats fed palm, corn or fish oil was similar, and higher than that found with cells from animals fed olive oil, and in this case these differences were mainly due to changes in the binding of the particles to the cells at 4 degrees C. Both excess low-density lipoprotein (LDL), which inhibits remnant uptake by the LDL receptor, and lactoferrin, which blocks the LDL receptor-related protein (LRP), were found to decrease the association of the remnants with cells from rats fed the low-fat and high-fat diets. However, in hepatocytes from animals given the low-fat diet, most of the differences between the various types of particle were retained in the presence of lactoferrin, but abolished in the presence of LDL. In contrast, in cells from rats fed the high-fat diets, the differences were reduced by both lactoferrin and LDL. These findings demonstrate that the hepatic uptake of chylomicron remnants is influenced both by the fatty acid composition of the particles, and by longer-term adaptive changes in liver tissue, and suggest that the former effects are mediated mainly by the LDL receptor, while the latter may involve both the LDL receptor and the LRP.