Atherogenic Low-density Lipoprotein Research Articles

C-reactive protein is an atheroprotective molecule

Abstract The co-localization of plasma C-reactive protein (CRP) and atherogenic low-density lipoprotein (LDL) at the atherosclerotic lesions raises the possibility of a role of CRP in the disease process. In vitro, in its native pentameric structural form, CRP does not bind to oxidized LDL. However, in its non-native pentameric structural form, CRP is capable of binding to oxidized LDL. It has been proposed that CRP changes its structure at sites of inflammation to gain the oxidized LDL-binding activity. In vivo, native CRP is neither pro-atherosclerotic nor atheroprotective in animal models of atherosclerosis. We assumed that native CRP shows no effect because inflammatory microenvironment in the arterial wall in animal models of atherosclerosis is not appropriate and, therefore, the structure of CRP remains unchanged. Accordingly, we hypothesized that a CRP mutant, generated by site-directed mutagenesis, capable of binding to oxidized LDL without the requirement of any further structural change should show an effect on the disease. In the current study, we evaluated the impact of such a CRP mutant on the development of atherosclerosis employing LDL receptor knockout mouse model of atherosclerosis. We found that there was a two-week delay in the development of atherosclerotic lesions in the aortic root of mice treated with mutant CRP compared to mice that did not receive CRP. The development of atherosclerotic lesions in the whole aorta was also reduced; there was 30% reduction in the size of lesions in mice treated with mutant CRP. Overall, the data indicate that CRP is indeed an atheroprotective molecule.

Serum lipoproteins are not associated with the severity of asthma

BackgroundAsthma is a chronic inflammatory disorder of the bronchi with a complicated and largely unknown pathogenesis. In this context, an emerging role is attributed to the apolipoproteins which serve as structural components of plasma lipoproteins. Low density lipoproteins (LDL) may be involved in the inflammatory pathways of the asthmatic airways; in particular, small dense LDL (sdLDL) particles were associated with increased oxidative susceptibility compared to medium and large sized LDL. In our previous study, we found a positive correlation between forced expiratory volume 1 s (FEV1) % predicted and larger LDL particles (LDL-1), and an inverse correlation between FEV1% predicted and sdLDL (LDL-3) in mild, untreated asthmatics. Although LDL appear to be important modulators of inflammation, data on their clinical implications are still lacking. ObjectiveThe aim of the study is to investigate whether LDL subclasses correlate with the severity of asthma, assuming that the atherogenic and most pro-inflammatory LDL contribute to ignite and perpetuate the airway inflammatory processes. MethodsThe study was conducted in one visit, and included clinical and lung functional assessments, as well as measurements of serum concentrations of the LDL subclasses. Non-denaturing, linear polyacrylamide gel electrophoresis was used to separate and measure LDL subclasses, with the LipoPrint© System (Quantimetrix Corporation, Redondo Beach, CA, USA). LDL subclasses were distributed as seven bands (LDL-1 to LDL-7), LDL-1 and -2 being defined as large LDL (least pro-inflammatory), and LDL-3 to 7 defined as sdLDL (most pro-inflammatory). Results70 asthmatics under inhaled treatment (M/F: 35/35) were enrolled; 10 healthy subjects (M/F: 3/7) served as controls. In the asthmatic group, FEV1% predicted was 81 ± 22% (mean ± SD), vital capacity (VC) % predicted was 97 ± 18%, and FEV1/FVC was 0.68 ± 0.1. The mean asthma control test (ACT) score was 18 ± 5. LDL-1 were significantly lower in asthmatics as compared to controls (18 ± 4% vs. 22 ± 4%, p = 0.008). On the contrary, LDL-2 (12 ± 4% vs. 12 ± 5%) and LDL-3 (3 ± 3% vs. 2 ± 2%) were not statistically different between the two groups; smaller subclasses were undetectable. To comply with the design of the study, subjects were classified according to their degree of severity into the 5 Global Initiative for Asthma (GINA) steps: Step 1 (M/F: 4/3, 44 ± 12 yrs), Step 2 (M/F: 1/2, 37 ± 11 yrs), Step 3 (M/F: 12/7, 47 ± 12 yrs), Step 4 (M/F: 8/15, 54 ± 12 yrs), and Step 5 (M/F: 7/9, 56 ± 9 yrs). None of the LDL subclasses showed significant differences between classes of severity: LDL-1 were 16.1 ± 5.6% in Step 1, 18 ± 2.8% in Step 2, 16.7 ± 3.7% in Step 3, 18 ± 3.3% in Step 4, and 19.5 ± 3.2% in Step 5 (p = NS); LDL2 were 14 ± 3.6%, 15 ± 3.4%, 12.4 ± 5.3%, 12.7 ± 4.4% and 11.3 ± 4.2%, respectively (p = NS); LDL3 were 5 ± 5.2%, 4.4 ± 2.6%, 3.3 ± 3.6%, 3.2 ± 2.6% and 2.4 ± 1.8%, p = NS. Finally, no relationship was detected between LDL subclasses and lung function parameters as well as the ACT scores. ConclusionsThe current findings confirm a role of LDL as a potential biomarker in the diagnostic process for asthma, and suggest that LDL cannot be used as marker of severity of the disease.

HUMORAL IMMUNITY TO THE DAMAGE OF LIPID METABOLISM IN PATIENTS WITH RENOCARDIAC SYNDROME

A total of 289 patients with chronic renocardiac syndrome, 204 of them with chronic glomerulonephritis and 85 diabetic nephropathy. The worsening of the lipid metabolism, depending on the degree of chronic renal failure (CRF), I noted in the degree of CKD, manifested increased low density lipoprotein (LDL) of 1.22 times (p=0.004), triglycerides (p=0.02), atherogenicity index (p<0.0001) and decreased high-density lipoprotein (HDL) cholesterol (p<0.001). The coefficient of LDL / HDL ratio was greatest in patients with CRF I, which indicates the most intense pro-atherogenic processes in these patients. The biological role of education lipoprotein immune complexes (LPIC) is confirmed by us revealed a statistically significant negative correlation between the ratio and the atherogenic LDL IgG (r=- 0,3; p=0.04), and LDL atherogenic factor IgM (r=-0,46, p=0.01) in patients with chronic renal failure group 1. A statistically significant negative correlation between daily proteinuria and LDL IgG, LDL IgM (r=-0,3; p=0,005; r=-0,4; p=0.004, respectively), which suggests the assumption of our damaging effect LPIC on the renal glomerulus.

The peptidylglycine-\u03b1-amidating monooxygenase (PAM) gene rs13175330 A>G polymorphism is associated with hypertension in a Korean population

BackgroundPeptidylglycine-α-amidating monooxygenase (PAM) may play a role in the secretion of atrial natriuretic peptide (ANP), which is a hormone involved in the maintenance of blood pressure (BP). The objective of the present study was to determine whether PAM is a novel candidate gene for hypertension (HTN).ResultsA total of 2153 Korean participants with normotension and HTN were included. Genotype data were obtained using the Korean Chip. The rs13175330 polymorphism of the PAM gene was selected from the ten single nucleotide polymorphisms (SNPs) most strongly associated with BP. The presence of the G allele of the PAM rs13175330 A>G SNP was associated with a higher risk of HTN after adjustments for age, sex, BMI, smoking, and drinking [OR 1.607 (95% CI 1.220–2.116), p = 0.001]. The rs13175330 G allele carriers in the HTN group treated without antihypertensive therapy (HTN w/o therapy) had significantly higher systolic and diastolic BP than the AA carriers, whereas the G allele carriers in the HTN group treated with antihypertensive therapy (HTN w/ therapy) showed significantly higher diastolic BP. Furthermore, rs13175330 G allele carriers in the HTN w/o therapy group had significantly increased levels of insulin, insulin resistance, and oxidized low-density lipoprotein (LDL) and significantly decreased LDL-cholesterol levels and LDL particle sizes compared to the AA carriers.ConclusionThese results suggest that the PAM rs13175330 A>G SNP is a novel candidate gene for HTN in the Korean population. Additionally, the PAM rs13175330 G allele might be associated with insulin resistance and LDL atherogenicity in patients with HTN.

Silencing ATG16L1 prevents potentiating effects of atherogenic low-density lipoprotein L5 on secretion of Von Willebrand factor

Background: Atherogenic L5 is significantly elevated in patients with acute ischemic stroke (AIS). Von Willebrand factor (VWF) has been considered to be a central player in thrombus formation and pathophysiology of AIS. Autophagy has emerged as critical in the process, mature and secretion of VWF in endothelial cell.

Desialated low density lipoproteins in
 human blood

The present article is a review of literature on circulating low-density lipoproteins (LDLP) which can induce accumulation of lipids (mainly, cholesterol), in a SMA(+) cell culture of normal human aortic intima. An attempt was undertaken to resolve the paradox of the absence of both native LDLP influence on intracellular lipid accumulation and modifications of in vitro obtained LDLP in the blood-vascular system. It was showed that atherogenic LDLPs are characterized by a number of changes in carbon, protein and lipid components which can be regarded as multiple modifications of LDLP taking place in human blood plasma. Multiply modified circulating LDLP possess of capacity to interact with various cell membrane receptors differing from B and E receptor, and with proteoglycans. Marked absorption of desiliated LDLPs by the cells simultaneous with a decrease in the degradation of apolipoproteins and cholesterol esters as well as induction of peresterification of free cholesterol leads to intracellular accumulation of esterified cholesterol. Formation of large LDLP-containing complexes especially circulating low-density lipoproteins can stimulate accumulation of lipids by smooth muscle cells of intima. Desiliated LDLPs stimulated cell proliferation and connective tissue matrix synthesis despite cholesterol ester accumulation. In conclusion, the authors of this article found and characterized natural multiply modified LDLPs that can be responsible for the symptoms of atherosclerosis at the cellular level.

ВПЛИВ ОСНОВНИХ ФАКТОРІВ РИЗИКУ НА ПЕРЕБІГ ІНФАРКТУ МІОКАРДА У ХВОРИХ ІЗ НАДМІРНОЮ МАСОЮ ТІЛА

Основними факторами ризику інфаркту міокарда, що сприяють виникненню та погіршують перебіг захворювання, є артеріальна гіпертензія, ожиріння, куріння, малорухливий спосіб життя, порушення ліпідного обміну та цукровий діабет 2 типу, особливо при їх поєднанні.Мета дослідження – дослідити особливості поширення основних факторів ризику серцево-судинної патології, їх вплив на перебіг та частоту розвитку ускладнень інфаркту міокарда у хворих із надлишковою масою тіла жителів Тернопільської області.Матеріали та методи. Обстежено 76 хворих на інфаркт міокарда віком від 39 до 85 років, яких методом конвертів поділили на 3 дослідні групи: перша група – 33 пацієнтів із інфарктом міокарда з надмірною масою тіла, друга група – 13 пацієнтів з інфарктом міокарда та з ожирінням І ст., третя – 10 хворих на інфаркт міокарда та з ожирінням ІІ–ІІІ ст. Контрольну групу склали 20 пацієнтів із нормальною масою тіла.Результати досліджень та їх обговорення. Встановлено, що найбільш поширеними факторами ризику серед хворих виявились артеріальна гіпертензія (у 97 % пацієнтів із надмірною масою тіла та у 100 % хворих з ожирінням) та цукровий діабет 2 типу (у 24 % хворих із надмірною масою тіла та у 60 % пацієнтів з ожирінням). Одночасно у хворих на інфаркт міокарда з надмірною масою тіла частіше, ніж у пацієнтів із нормальною масою тіла, зустрічались підвищення найбільш атерогенного класу – холестерину ліпопротеїдів низької щільності та зниження антиатерогенного класу холестерину ліпопротеїдів високої щільності. У пацієнтів з ожирінням ІІ–ІІІ ст. достовірно частіше спостерігалась гіпертригліцеридемія (р=0,003).Висновки. Аналіз катамнезу засвідчив, що найчастішими ускладненнями у хворих на інфаркт міокарда з надлишковою масою тіла виявились серцева астма, набряк легень, гостра аневризма лівого шлуночка та епістенокардитичний перикардит.

Multiple-modified Low-Density Lipoprotein as Atherogenic Factor of Patients' Blood: Development of Therapeutic Approaches to Reduce Blood Atherogenicity.

Generally, atherosclerosis first occurs by the way of accumulation of intracellular and extracellular lipids in the arterial intima. Foam cells, overloaded by lipids, are the essential harbinger of the coronary artery disease. It should be noted that lipids that are usually composed of bulk of the intracellular lipids found in human arterial cells originate from low-density lipoprotein (LDL) circulating in human blood. Nonetheless, many efforts to force cells to accumulate cholesteryl esters under the influence of native LDL have been unsuccessful. Whilst LDL modified in vitro (exposed to malondialdehyde, oxidized with ions of transition metals, acetylated, etc.) promoted accumulation of lipids in cells, all the attempts made for the sake of hunting down such LDLs in the bloodstream still do not provide confident conclusions. Therefore, a controversy arose: firstly, lipids from the cells of vascular wall have proved to be descending from LDL; secondly, foam cells do not form under the influence of native LDL in vitro (i.e. no visible intracellular lipid deposition observed); thirdly, chemically manipulated LDL seems to possess atherogenic properties. Acetylated LDL was not found in the bloodstream; similarly, the existence of oxidized LDL in the circulation remains controversial. Such a conundrum sparked a thorough investigation, leading to some interesting results. Modified desialylated LDL in human blood stream has been identified, which was able to promote lipid deposition in cultured cells. Such an LDL has been isolated, displaying atherogenic properties. The atherogenic LDL seems to deviate in multiple features from its non-atherogenic counterparts: carbohydrate, protein, and lipid moieties which were mangled. Such multiple LDL transformations take place in human blood stream and seem to denote a succession of events forcing the particle to become atherogenic: desialylation, lipid loss, shrinkage, rising of surface electronegative charge, etc. On top of the fat deposition in cells, multiple modifications of LDL as well as some other deleterious effects, like cell proliferation and fibrosis, seem to be part of the chain of events finally unfolding into a full-scale atherosclerotic lesion.

Impact of hormonal contraception and weight loss on high-density lipoprotein cholesterol efflux and lipoprotein particles in women with polycystic ovary syndrome.

To study the effects of oral contraceptive pills (OCP), the first-line treatment for PCOS, on high-density lipoprotein cholesterol (HDL-C) function (reverse cholesterol efflux capacity) and lipoprotein particles measured using nuclear magnetic resonance spectroscopy in obese women. Secondary analysis of a randomized controlled trial (OWL-PCOS) of OCP or Lifestyle (intensive Lifestyle modification) or Combined (OCP + Lifestyle) treatment groups for 16 weeks. Eighty-seven overweight/obese women with PCOS at two academic centres. Change in HDL-C efflux capacity and lipoprotein particles. High-density lipoprotein cholesterol efflux capacity increased significantly at 16 weeks in the OCP group [0·11; 95% confidence interval (CI) 0·03, 0·18, P = 0·008] but not in the Lifestyle (P = 0·39) or Combined group (P = 0·18). After adjusting for HDL-C and TG levels, there was significant mean change in efflux in the Combined group (0·09; 95% CI 0·01, 0·15; P = 0·01). Change in HDL-C efflux correlated inversely with change in serum testosterone (rs = -0·21; P = 0·05). In contrast, OCP use induced an atherogenic low-density lipoprotein cholesterol (LDL-C) profile with increase in small (P = 0·006) and large LDL-particles (P = 0·002). Change in small LDL-particles correlated with change in serum testosterone (rs = -0·31, P = 0·009) and insulin sensitivity index (ISI; rs = -0·31, P = 0·02). Both Lifestyle and Combined groups did not show significant changes in the atherogenic LDL particles. Oral contraceptive pills use is associated with improved HDL-C function and a concomitant atherogenic LDL-C profile. Combination of a Lifestyle program with OCP use improved HDL-C function and mitigated adverse effects of OCP on lipoproteins. Our study provides evidence for use of OCP in overweight/obese women with PCOS when combined with Lifestyle changes.

SUBFRACTION DISTRIBUTION OF APO B-CONTAINING LIPOPROTEINS DEPENDING ON THE ACHIEVEMENT OF THE TARGET LEVEL OF LOW DENSITY LIPOPROTEINS UNDER STATINS THERAPY IN PATIENTS WITH CORONARY ATHEROSCLEROSIS

Aim. To reveal whether there are differences in subfractional distribution of apo B-containing lipoproteins in men and women with coronary atherosclerosis treated with statins depending on low density lipoprotein (LDL) cholesterol level. Material and methods . Patients aged 33-85 years with angiography documented coronary atherosclerosis were included into the study (n=133): 97 men (mean age 61±9.0 years) and 36 postmenopausal women (mean age 65±9.3 years). Patients were on statin therapy at least 6 months before admission: atorvastatin (10-40 mg/day), simvastatin (20-40 mg/day), rosuvastatin (10-40 mg/day) and pravastatin (20 mg/day). Subfractional apo B-containing lipoproteins distribution was analyzed by electrophoresis in a 3% polyacrylamide gel. Results. Men achieving target LDL cholesterol level (<2.5 mmol/l) as compared with those with higher LDL cholesterol level alongside with decreased proatherogenic lipids and apolipoproteins, had less atherogenic LDL subfractional profile: lower portion of LDL 2 (7.3±3.4 и 9.9±3.9%, p<0.01), small dense LDL 3 (1.3±1.2 и 2.2±2.2%, р<0.05), LDL 4 (0.2±0.2 и 0.3±0.5%, p<0.05), and concentration of cholesterol in this subfrtactions. These differences were associated with elevated mean size of LDL particles (270.8±3.0 vs 268.8±3.9 A, p<0,01). On the other hand, women, despite achieving target LDL cholesterol level, had elevated apo B level and apo B/AI ratio without any differences in subfractional profile of low densities lipoproteins. Conclusion. In patients with coronary atherosclerosis treated with statins, antiatherogenic shifts in apo B-containing lipoproteins, decrease of cholesterol concentration subfractions coupled by elevation of mean LDL particle size were found only in men who reached target LDL cholesterol level.

Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations

Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.

Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia.

Normalization of hypercholesterolaemia, inflammation, hyperglycaemia, and obesity are main desired targets to prevent cardiovascular clinical events. Here we present a novel regulator of cholesterol metabolism, which simultaneously impacts on glucose intolerance and inflammation. Mice deficient for oxygen sensor HIF-prolyl hydroxylase 1 (PHD1) were backcrossed onto an atherogenic low-density lipoprotein receptor (LDLR) knockout background and atherosclerosis was studied upon 8 weeks of western-type diet. PHD1-/-LDLR-/- mice presented a sharp reduction in VLDL and LDL plasma cholesterol levels. In line, atherosclerotic plaque development, as measured by plaque area, necrotic core expansion and plaque stage was hampered in PHD1-/-LDLR-/- mice. Mechanistically, cholesterol-lowering in PHD1 deficient mice was a result of enhanced cholesterol excretion from blood to intestines and ultimately faeces. Additionally, flow cytometry of whole blood of these mice revealed significantly reduced counts of leucocytes and particularly of Ly6Chigh pro-inflammatory monocytes. In addition, when studying PHD1-/- in diet-induced obesity (14 weeks high-fat diet) mice were less glucose intolerant when compared with WT littermate controls. Overall, PHD1 knockout mice display a metabolic phenotype that generally is deemed protective for cardiovascular disease. Future studies should focus on the efficacy, safety, and gender-specific effects of PHD1 inhibition in humans, and unravel the molecular actors responsible for PHD1-driven, likely intestinal, and regulation of cholesterol metabolism.

PCSK9 Association With Lipoprotein(a).

Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associated with Lp(a) in plasma. Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dL) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via coexpression of human apo(a) and human apolipoprotein B). We show that PCSK9 is physically associated with Lp(a) in vivo using 3 different approaches: (1) analysis of Lp(a) fractions isolated by ultracentrifugation; (2) immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (3) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only, and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) versus low-density lipoprotein (1.7-fold increase) was seen in subjects with high Lp(a) and normal low-density lipoprotein. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels. Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk.

MiRNA regulation of LDL-cholesterol metabolism

In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non-coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

Z-Scan Analysis: a New Method to Determine the Oxidative State of Low-Density Lipoprotein and Its Association with Multiple Cardiometabolic Biomarkers

The great atherogenic potential of oxidized low- density lipoprotein has been widely described in the literature. The objective ofthisstudy was to investigate whether the state of oxidized low-density lipoprotein in human plasma mea- sured by the Z-scan technique has an association with differ- ent cardiometabolic biomarkers. Total cholesterol, high- density lipoprotein cholesterol, triacylglycerols, apolipopro- tein A-I and apolipoprotein B, paraoxonase-1, and glucose were analyzed using standard commercial kits, and low- density lipoprotein cholesterol was estimated using the Friedewald equation. A sandwichenzyme-linked immunosor- bent assay was used to detect electronegative low-density li- poprotein. Low-density lipoprotein and high-density lipopro- tein sizes were determined by Lipoprint ® system. The Z-scan technique was usedto measure the non-linear optical response oflow-densitylipoproteinsolution.Principalcomponentanal- ysis and correlations were used respectively to resize the data from the sample and test association between the θ parameter, measured with the Z-scan technique, and the principal com- ponent. A total of 63 individuals, from both sexes, with mean age 52 years (±11), being overweight and having high levels of total cholesterol and low levels of high-density lipoprotein cholesterol, were enrolled in this study. A positive correlation betweenthe θparameter and moreanti-atherogenicpattern for cardiometabolic biomarkers together with a negative correla- tion for an atherogenic pattern was found. Regarding the pa- rameters related with an atherogenic low-density lipoprotein profile, the θ parameter was negatively correlated with a more atherogenic pattern. By using Z-scan measurements, we were able to find an association between oxidized low-density lipo- protein state and multiple cardiometabolic biomarkers in sam- ples from individuals with different cardiovascular risk factors.

Cellular Model of Atherogenesis Based on Pluripotent Vascular Wall Pericytes.

Pericytes are pluripotent cells that can be found in the vascular wall of both microvessels and large arteries and veins. They have distinct morphology with long branching processes and form numerous contacts with each other and with endothelial cells, organizing the vascular wall cells into a three-dimensional network. Accumulating evidence demonstrates that pericytes may play a key role in the pathogenesis of vascular disorders, including atherosclerosis. Macrovascular pericytes are able to accumulate lipids and contribute to growth and vascularization of the atherosclerotic plaque. Moreover, they participate in the local inflammatory process and thrombosis, which can lead to fatal consequences. At the same time, pericytes can represent a useful model for studying the atherosclerotic process and for the development of novel therapeutic approaches. In particular, they are suitable for testing various substances' potential for decreasing lipid accumulation induced by the incubation of cells with atherogenic low-density lipoprotein. In this review we will discuss the application of cellular models for studying atherosclerosis and provide several examples of successful application of these models to drug research.

A molecular dynamics investigation on the inhibition mechanism of cholesteryl ester transfer protein by Anacetrapib

A decrease in high-density lipoprotein (HDL) level and an increase in atherogenic low-density lipoprotein (LDL) concentration in plasma are involved in the progress of atherosclerosis and incidence of cardiovascular diseases. Cholesteryl ester transfer protein (CETP) passes cholesteryl ester and triglyceride molecules through a hydrophobic tunnel between lipoproteins and via that decreases the HDL/LDL ratio in plasma. Thus, inhibition of CETP activity by specific inhibitors could diminish atherosclerosis occurrence. Anacetrapib as a specific reversible inhibitor of CETP by stabilizing CETP–HDL complex significantly increases the HDL/LDL ratio in plasma. For better understanding the mechanism of CETP inhibition by Anacetrapib, after docking Anacetrapib against a CETP structure, molecular dynamics simulation of CETP and CETP–Anacetrapib in an explicit water cage was performed. Analyses of acquired trajectories show that Anacetrapib increases fluctuation of residues 421–442 of CETP through hydrophobic interactions and thus disrupts the integrity of an α-helix (helix B) structure in the C-terminal concave surface. Creation of a hinge by defeat of the helix B in the C-terminal of CETP, where CETP interacts with LDL, results in missing of an α-helix (residues 436–440) and conversion of banana-shaped CETP to a hemisphere conformation. According to the obtained results, bending of the CETP structure and conversion of the secondary structure in the C-terminal domain in the presence of Anacetrapib may destabilize CETP–VLDL complex and through that shift the dynamics of CETP to the formation of the CETP–HDL complex.

Inhibitory Effect of Polyethylene Oxide and Polypropylene Oxide Triblock Copolymers on Aggregation and Fusion of Atherogenic Low Density Lipoproteins.

Triblock copolymers of poly(ethylene oxide) and poly(propylene oxide) (so-called pluronics) were shown to influence the aggregation and fusion of atherogenic low density lipoproteins (atLDL) and be able to inhibit these processes. The character of the influence and the degree of the stabilizing effect depended on the structure, relative hydrophobicity, and concentration of the copolymer. Pluronics L61, P85, and L64 characterized by the hydrophilic-lipophilic balance (HLB) value from 3 to 16 had the greatest ability to suppress the aggregation of atLDL. Pluronic L81 with the higher hydrophobicity (HLB = 2) partially inhibited atLDL aggregation at low concentrations but stimulated it at high concentrations. The influence of pluronics did not have a direct connection with their ability for micelle formation, but it was realized through individual macromolecules. We suppose that effects of pluronics could be due to their interaction with the lipid component of LDL and to a possible influence of these copolymers on the structure and hydrophilic-lipophilic characteristics of lipoproteins.

Abstract 127: Structure and Function Relationship of Phospholipid Transfer Protein in Lipid Transfer Activity Revealed by Electron Microscopy

Human phospholipid transfer protein (PLTP) mediates the transfer of lipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would be an important step toward the understanding and regulation of PLTP for treating cardiovascular diseases, hypoalphalipoproteinemia and hyperalphalipoproteinemia. Using electron microscopy, negative-staining, and single-particle image processing, we discovered that PLTP penetrates each class of HDL, LDL and liposome independently, and also bridges a ternary complex with one of its distal end-domains penetrating into HDL and another distal domain interacting with LDL. These new insights into PLTP interaction with lipoproteins and liposomes provide a molecular basis for analyzing PLTP-dependent lipid transfer between lipoprotein particles.

APSC2015-1153 The Effects of Weight Gain After Smoking Cessation on an Atherogenic Low-Density Lipoprotein

APSC2015-1153 The Effects of Weight Gain After Smoking Cessation on an Atherogenic Low-Density Lipoprotein