Search

Atherosclerosis is responsible for most cardiovascular disease (CVD) and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox) produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS) have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB) is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ) is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG). Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS) in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.

Background/Aims: Recent studies have indicated that CD38 gene deficiency results in dedifferentiation or transdifferentiation of arterial smooth muscle cells upon atherogenic stimulations. However, the molecular mechanisms mediating this vascular smooth muscle (SMC) phenotypic switching remain unknown. Methods & Results: In the present study, we first characterized the phenotypic change in the primary cultures of coronary arterial myocytes (CAMs) from CD38-/- mice. It was shown that CD38 deficiency decreased the expression of contractile marker calponin, SM22α and α-SMA but increased the expression of SMC dedifferentiation marker, vimentin, which was accompanied by enhanced cell proliferation. This phenotypic change in CD38-/- CAMs was enhanced by 7-ketocholesterol (7-Ket), an atherogenic stimulus. We further found that the CD38 deficiency decreased the expression and activity of nuclear factor E2-related factor 2 (Nrf2), a basic leucine zipper (bZIP) transcription factor sensitive to redox regulation. Similar to CD38 deletion, Nrf2 gene silencing increased CAM dedifferentiation upon 7-Ket stimulation. In contrast, the overexpression of Nrf2 gene abolished 7-Ket-induced dedifferentiation in CD38-/- CAMs. Given the sensitivity of Nrf2 to oxidative stress, we determined the role of redox signaling in the regulation of Nrf2 expression and activity associated with CD38 effect in CAM phenotype changes. It was demonstrated that in CD38-/- CAMs, 7-Ket failed to stimulate the production of O2-., while in CD38+/+ CAMs 7-Ket induced marked O2-. production and enhancement of Nrf2 activity, which was substantially attenuated by NOX4 gene silencing. Finally, we demonstrated that 7-Ket-induced and NOX4-dependent O2-. production was inhibited by 8-Br-cADPR, an antagonist of cADPR or NED-19, an antagonist of NAADP as product of CD38 ADP-ribosylcyclase, which significantly inhibited the level of cytosolic Ca2+ and the activation of Nrf2 under 7-Ket. Conclusion: Taken together, these results suggest that CD38 activity is required for 7-Ket-induced Ca2+ and consequently O2-. production in CAMs, which increases Nrf2 activity to maintain their differentiated status. When CD38 gene expression and function are deficient, the Nrf2 activity is suppressed, thereby leading to phenotypic switching of CAMs.

Objective:: To study the differences between the lipid profiles of the subjects whose parents are having known non-modifiable risk factors such as obesity, hypertension (HTN), myocardial infarction and diabetes, and compare them with the lipid profiles of the subjects whose parents are not having those risk factors. Methods:: A total of 402 subjects were recruited to this study. A detailed questionnaire which included information on the past medical history, height, weight, blood pressure, physical activity, smoke, alcohol, family history of coronary heart disease, HTN, diabetics and obesity. Basic demographic data and dietary habits were completed by all participants. Blood samples were obtained from all subjects after 14 h. Lipid profiles were analyzed using automated analyzer. The results were analyzed using SPSS software packages. Results:: The mean body mass index of the population was well below the cut-off value of obesity (>24.5 kg/m2) and high risk of future cardiovascular disorder (CVD) events in this age group. The mean levels of total cholesterol (TC), triglycerides (TG) and TC/high density lipoprotein (HDL) were less than the risk levels indicative of future CVD events according to the ATP III cut-off values. However the mean HDL level in our population was slightly greater than the cut-off value while the mean low density lipoprotein level was almost similar to the risk level. Differences were observed when the subjects without history of maternal obesity were compared with subjects with history of maternal obesity. The greater percentage of subjects who are having risk levels of body mass index, TC, low density lipoprotein, TG, and TC/HDL indicated that maternal obesity contributed to the greater susceptibility of developing CVD risk in their offspring. Conclusions:: Advancing age may result in changes that could be atherogenic in the future. Such atherogenic changes have already initiated when the subjects are about 21 years old. The incidence of atherogenic changes is far greater when mothers who are having any of the risk factors such as obesity, diabetes, HTN and myocardial infarction than that fathers who are having similar risk factors.

Background: The global burden of coronary heart disease (CHD) is estimated to be the highest on the Indian subcontinent. The pathophysiology of this increased risk is complex, multifactorial, and its magnitude increases with migration from India to Britain. Haemoglobin disorders, which also frequent this ethnic group, have been linked to cardiovascular disease. We investigated the impact of migration and nutritional intake on haematological parameters amongst South Asians, with a focus on their relation to molecular indices of oxidative atherogenesis. Methods: Haematology, diet, oxidised low-density lipoprotein (LDL), and serum paraoxonase activity were measured in 230 migrant Indian Gujaratis (Britain), and 305 matched contemporaries living in rural villages (India). Results: Median levels of haemoglobin were higher amongst migrant men (14.5 µmol/l) compared to rural men (15.0 µmol/l, P=0.004) and higher in migrant women (12.7 µmol/l) compared to rural women (11.8 µmol/l, P

Acrolein, a highly toxic α, β‐unsaturated aldehyde, promotes the progression of atherosclerosis in association with inflammatory signaling pathway and reverse cholesterol transport (RCT) process. Additionally, hepatic flavin containing monooxygenase 3 (FMO3) is involved in the pathogenesis of atherosclerosis by regulating cholesterol metabolism. Hydroxytyrosol (HT), as a major phenolic compound in olive oil, exerts anti‐inflammatory and anti‐atherogenic activities in vitro and animal models. The current study was designed to evaluate whether FMO3 participated in pro‐atherogenic process by acrolein and HT showed protective effect during this process. Here, endothelial cells and macrophage Raw264.7 cells were used as the cell models. Following oxidized low‐density lipoprotein (OX‐LDL) treatment, acrolein exposure promoted foam cells formation in macrophage Raw264.7 cells. The expression of FMO3 and inflammatory makers such as phospho‐NF‐κB, IL‐1β, TNFα as well as IL‐6 were significantly increased. However, ATP‐binding cassette transporters subfamily A member 1 (ABCA1), a major transporter in RCT process, was repressed by acrolein. In addition, FMO3 knockdown could suppress inflammatory markers and promote ABCA1 expression. Hydroxytyrosol (HT) was observed to reduce lipid accumulation, FMO3 expression as well as inflammatory response. Moreover, it promoted ABCA1 expression. Therefore, our findings indicated that acrolein‐enhanced atherogenesis by increasing FMO3 which increased inflammatory responses and decreased ABCA1 in vitro can be alleviated by HT, which may have a therapeutic potential for the treatment of atherosclerosis. Acrolein enhanced atherogenesis by increasing FMO3. FMO3 increased inflammatory responses and decreased ABCA1 in vitro. Hydroxytyrosol could alleviate acrolein‐induced atherogenesis. [ABSTRACT FROM AUTHOR]

Abstract The events that trigger early onset of atherosclerotic lesion formation are poorly understood. Initially, microscopic atherosclerotic lesions appear in the aortic root in 10-week-old apoE-knockout mice that are fed normal chow. Using proteome and immunohistochemical analyses, we investigated proteins in aortic media whose expression changes in athero-prone regions at the beginning of lesion formation. Protein profiles of the root/arch and thoracic/abdominal regions of aortas in 10-week-old apoE-knockout mice were analyzed using 2D-gel electrophoresis. Proteins in 81 spots with different abundance were identified. Among them, we focused on proteins related to oxidative stress and smooth muscle cells (SMCs). The level of peroxiredoxin 2 (Prx2), a major cellular antioxidant enzyme that reduces hydrogen peroxide, was lower in aortic root/arch compared with thoracic/abdominal aorta. Immunohistochemical staining demonstrated that Prx2 expression in SMCs in the aortic root was high at 4 weeks and decreased at 10 weeks in apoE-knockout mice, while Prx2 expression in the aorta was unchanged in wild-type mice. The level of Prx2 expression correlated positively with the SMC differentiation markers, α-smooth muscle actin and transgelin, suggesting that a decline in Prx2 expression accompanies SMC dedifferentiation. Accumulated acrolein-modified proteins and the infiltration of macrophages in aortic media were observed in areas with low Prx2 expression. These results showed that Prx2 expression declines in athero-prone aortic root before lesion formation, and this reduction in Prx2 expression correlates with lipid peroxidation, SMC dedifferentiation, and macrophage recruitment. Graphical abstract fx1 Highlights • Peroxiredoxin 2 (Prx2) decreased at the beginning of atherosclerotic lesion formation in aortic media in apoE-KO mice. • Local aortic regions with low Prx2 expression accumulate oxidation products. • The concomitant reduction of Prx2, α-SMA and transgelin expressions suggests Prx2 relates to SMC dedifferentiation. • Infiltration of macrophages into media is observed at the site of Prx2 reduction. • Prx2 reduction at small regions is a potential triggering event at the early onset of atherogenesis. [ABSTRACT FROM AUTHOR]

Given its role in many biochemical processes essential to life, cholesterol remains a topic of intense research. Of all the plasma lipids, cholesterol is distinctive because it is a precursor to steroidogenic molecules, some of which regulate metabolism, and its blood concentration in the form of low- and high-density lipoprotein cholesterol (HDL-C) are positive and negative risk factors for atherosclerotic cardiovascular disease (ASCVD). New research, however, has challenged the widely held belief that high HDL-C levels are atheroprotective and is showing that both low and high plasma HDL-C levels confer an increased risk of ASCVD. Furthermore, it is disputing the widely cited mechanism involved in reverse cholesterol transport. This review explores the evolution of cholesterol research starting with the Gofman and Framingham studies, the development of traditional and emerging lipid-lowering therapies, and the role of reverse cholesterol transport in HDL cardioprotection. [ABSTRACT FROM AUTHOR]

Dysregulated free cholesterol (FC) metabolism has been implicated in nearly all stages of atherosclerosis, the underlying cause of most cardiovascular disease. According to a widely cited model, the burden of macrophage FC in the arterial wall is relieved by transhepatic reverse cholesterol transport (RCT), which comprises three successive steps: (1) macrophage FC efflux to high-density lipoprotein (HDL) and/or its major protein, apolipoprotein AI; (2) FC esterification by lecithin:cholesterol acyltransferase (LCAT); and (3) HDL-cholesteryl ester (CE) uptake via the hepatic HDL-receptor, scavenger receptor class B type 1 (SR-B1). Recent studies have challenged the validity of this model, most notably the role of LCAT, which appears to be of minor importance. In mice, most macrophage-derived FC is rapidly cleared from plasma (t1/2 < 5 min) without esterification by hepatic uptake; the remainder is taken up by multiple tissue and cell types, especially erythrocytes. Further, some FC is cleared by the nonhepatic transintestinal pathway. Lastly, FC movement among lipid surfaces is reversible, so that a higher-than-normal level of HDL-FC bioavailability-defined by high plasma HDL levels concurrent with a high mol% HDL-FC-leads to the transfer of excess FC to cells in vivo. SRB1-/- mice provide an animal model to study the mechanistic consequences of high HDL-FC bioavailability that provokes atherosclerosis and other metabolic abnormalities. Future efforts should aim to reduce HDL-FC bioavailability, thereby reducing FC accretion by tissues and the attendant atherosclerosis. [ABSTRACT FROM AUTHOR]

Platelet markers [soluble p selectin (sP-selectin) and soluble CD40 ligand (sCD40L)] are associated with platelet activation and cardiovascular risk. Both policosanol and 10-dehydrogingerdione are natural products with proven CETP inhibitory and antiatherogenic effects. Present work aimed mainly to investigate the levels of platelet activation biomarkers in the serum of dyslipidemic rabbits and the potential of these phytochemicals either alone or in a combination form to protect against atherogenicity. Additionally, this work clarified their effect on PCSK9, a key player in atherosclerosis progression. Daily administration of policosanol and/or 10-dehydrogingerdione at a dose level 10 mg/kg bw resulted in a CETP inhibitory activity, increasing HDL-C level. This protective effect was associated with improvement in lipid profile components and a reduction in PCSK9 level. Interestingly, this combination strengthened the CETP inhibitory activity of these phytochemicals, leading to a greater increase in serum HDL-C level than monotherapy. However, this combination did not enhance the reduction in PCSK9 level. Both drugs also decreased platelet activation and inflammation markers such as sCD40L, sP-selectin, and interferon-gamma (IFN-γ), and their combination showed a synergistic effect. Therefore, such phytochemicals may be regarded as promising agents in the protection against atherothrombosis risk. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Lipidomic profiles of raw and baked goat and sheep meat have been studied. • Anti-atherogenic activities of polar lipids of meat samples have been evaluated. • The most bioactive fractions of polar lipids have been studied by LC–MS. • The anti-anterogenic activities are due to phosphatidylcholine derivatives. • Sheep and goat meat are excellent sources of bioactive lipids against CVDs. Abstract The lipidomic profiles of goat and sheep meat were studied. Polar lipid fractions of raw and baked meat samples were tested for their in vitro anti-atherogenic properties. The total lipid (TL) content was extracted using the Bligh-Dyer method and was subsequently separated into total polar lipids (TPL) and total neutral lipids (TNL). The fatty acid profiles of the TPL and TNL of all three samples were determined by GC-FID. The TPL of all samples were further separated by preparative TLC into their constituent phospholipid and sphingolipid fractions. In all samples, polar lipid fraction 3 had a similar R f value to phosphatidylcholine. These phosphatidylcholine fractions were tested for their in vitro capacity to inhibit platelet-activating factor (PAF) induced platelet aggregation (anti-inflammatory activity) using human platelets. The phospholipid content of each fraction 3 was determined using LC–MS. These results provide a novel insight into the structure of phosphatidylcholine derivatives in goat and sheep meat and highlight the nutritional value of these meats in terms of their antithrombotic and cardioprotective properties before and after the baking process. [ABSTRACT FROM AUTHOR]

Background and Aims Atherosclerosis as an inflammatory disease involved in the etiology of cardiovascular disease worldwide, in our days demands an array of different therapeutic approaches in order to soon be able to visualize an effective prevention. Based on an immunotherapeutic approach, we designed a non-invasive vaccine (HB-ATV-8), contained in a micellar nanoparticle composed of lipids and a peptide segment derived from the C-terminus of the cholesterol-ester transfer protein (CETP). Now we extend our successful proof of concept from the rabbit to a porcine model and investigated its effect in an attempt to undoubtedly establish the efficacy of vaccination in a model closer to the human. Methods A preclinical trial was designed to study the efficacy of vaccine HB-ATV-8 in pigs (Large White × Landrace). Male experimental animals were fed with standard diet (control), high fat diet (HFD) or the same HFD but treated with HB-ATV-8 (HFD + Vaccine) applied nasally for up to 7 months. All biochemical and enzymatic analyses were performed in peripheral venous blood and thoracic aorta and liver samples examined using conventional, two-photon excitation and second harmonic generation microscopy to identify atherosclerotic and hepatic lesions. mRNA concentrations for KLF2 , ACTA2 , SOD1, COL1A1 genes and protein levels for PPARα and ABCA1 were quantified in aorta and liver respectively using qPCR and Western blot analysis. Results The administration of vaccine HB-ATV-8 induced anti-CETP IgG antibodies and reduced atherosclerotic and hepatic lesions promoted by the high fat diet. In addition, plasma triglyceride levels of vaccine treated pigs fed the HFD were similar to those of control group, in contrast to high concentrations reached with animals exclusively fed with HFD. Moreover, HFD promotes a tendency to decrease hepatic PPARα levels and increase in aorta gene expression of KLF2 , ACTA2 , SOD1 and COL1A1 , while vaccine application promotes recovery close to control values. Conclusions Vaccine HB-ATV-8 administration constitutes a promissory preventive approach useful in the control of atherogenesis and fatty liver disease. The positive results obtained, the non-invasive characteristics of the vaccine, the simple design employed in its conception and its low production cost, support the novelty of this therapeutic strategy designed to prevent the process of atherogenesis and control the development of fatty liver disease. [ABSTRACT FROM AUTHOR]

The association of brain-derived neurotrophic factor (BDNF) as a member of neurotrophin family and metabolic syndrome (MetS) has been proposed, however basic evidence necessary to prove (or disprove) this association in non-genetic animal model is rare. Therefore, we investigated the alteration of encephalic BDNF gene expression in a mouse model of high-fat diet (HFD) induced MetS. To translate MetS, male NMRI mice (9 weeks old; N = 13) fed on a HFD including suet powder (37.50%) and granulated sugar (19.85%) while control mice were fed a diet contained suet powder (6.25%) and granulated sugar (49.09%). We monitored the development of MetS by measuring fasting blood sugar (FBS) and lipid (total cholesterol (TC) and triacylglycerol (TGs)) and lipoprotein (high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C)) profiles, atherogenic index (AI), and somatic indices after 1 and 3 months of dietary interventions. The HFD intake led to increased body weight, liver weight, FBS, TC, and decreased HDL-C as compared to chow diet in mice after first month of dietary intervention. The increased FBS, body weight, abdominal fat mass, TGs, TC, and VLDL-C and decreased HDL-C were observed in HFD-fed mice as compared to those of chow-fed mice at 3th month. The statistical comparison of two HFD groups in two time intervals of 1st and 3th month confirmed that our HFD-induced MetS model was reliable because FBS, TGs and VLDL-C, TC, and AI have been increased significantly during selected time intervals. The AI increased significantly in HFD-fed mice compared to chow-fed mice after 3 months. The AI in HFD-fed mice treated with HFD for 3 months was increased significantly as compared to mice fed HFD for 1 month. Our diet-induced model more closely mimics the changes observed in human MetS and showed that encephalic BDNF gene in mice fed HFD was under-expressed by 0.30 fold with respect to chow-fed mice after 3 months of dietary intervention. [ABSTRACT FROM AUTHOR]

Abstract Background For a long time, our major understanding of the spleen is to function as a blood filter for the removal of aged erythrocytes and circulating microorganisms. Splenectomy, therefore, has been widely performed in case of trauma and a variety of hematologic disorders. Although some studies have indicated an increased rate of developing hyperlipidemia and atherosclerotic cardiovascular diseases in splenectomized patients, our recognition of the splenic regulation on lipid metabolism and atherogenesis is still lacking. Here we explored this issue in Apoe deficient (Apoe−/−) mice fed on an atherogenic diet containing 0.5% cholesterol and 20% fat. Methods 7-week-old male Apoe−/− mice were randomly divided into splenectomy group and sham operation group. After 1-week recovery from the surgery, mice were subjected to the atherogenic diet for the next 8 weeks. Results The atherogenic diet induced a severe hypercholesterolemia (about 1500 mg/dl), steatohepatitis and accelerated atherogenesis in the Apoe−/− mice. Splenectomy, compared to sham operation, did not alter plasma lipid levels or lipoprotein profiles; it also did not alter hepatic or adipose lipid deposition. Meanwhile, splenectomy did not alter atherosclerotic plaque burden or composition; it also did not alter aortic gene expression associated with macrophage inflammatory responses. Conclusions Our data suggested that splenectomy had no significant impacts on lipid metabolism and atherogenesis in Apoe−/− mice fed on a severe atherogenic diet. Highlights • Apoe−/− mice were splenectomized or sham-operated and fed a severe atherogenic diet • Splenectomy did not alter plasma lipid levels or lipoprotein profiles • Splenectomy did not alter hepatic or adipose lipid deposition • Splenectomy did not alter atherosclerotic plaque burden or composition • Splenectomy did not alter aortic gene expression related to macrophage inflammation [ABSTRACT FROM AUTHOR]

Purpose: Adiponectin an adipokine, produced by mature adipocyte, has an important effect on several aspects of endothelial function, including leukocyte adhesion (mediated by adhesion molecules like intercellular adhesion molecule 1 (ICAM1) endothelial cell selective adhesion molecule ESAM). Recently, it has been linked to vascular endothelial growth factor (VEGF)-modulated angiogenesis. ESAM might also be involved in modulating VEGF-dependent actions. We studied relationship of adiponectin to ESAM, ICAM1, and VEGF in type 2 diabetic patients (T2DP) with or without microvascular complications.Methods: Incident T2DP referred for nephrologic evaluation were included (patients with no nephropathy or stage 1-4 nephropathy). T2DP with stage 5 chronic kidney disease (CKD) were selected from a dialysis center. Clinical, standard laboratory assessment and adiponectin, ESAM, ICAM1, and VEGF (ELISA) were recorded.Results: Eighty-seven patients were included, 15 had no CKD, 30 with stage 1 or 2 CKD, 20 with stage 3 or 4 CKD and 22 patients on dialysis. ESAM was higher in patients with CKD than in those without CKD (p = 0.02), adiponectin, ICAM1, and VEGF were similar. Adiponectin correlated in univariate analysis to ESAM (r = 0.32, p = 0.002), ICAM1 (r = 0.23, p = 0.038), and CRP (r = 0.31, p = 0.012), and inversely to serum albumin (r = − 0.57, < 0.0001). In predialysis patients, adiponectin also correlated to albuminuria (r = 0.54, p < 0.0001) and glomerular filtration rate (r = − 0.46, p = 0.0001). In multivariate regression ESAM (p = 0.04), VEGF (p = 0.03), and albumin (p < 0.0001) are significant predictors of adiponectin. None of these cytokines were different when comparing patients with and without retinopathy.Conclusion: Adiponectin is directly linked to adhesion molecules and VEGF in T2DP. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSP or stress proteins) are intracellular molecules that participate in physiological cell metabolism and growth, although they are known to be involved in many stress conditions. Statins inhibit the action of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), which is important in the synthesis of cholesterol and essential isoprenoid intermediates, thereby lowering circulating low-density lipoprotein cholesterol (LDL), a major risk factor for cardiovascular disease (CVD). This review provides new insights into the mechanisms of action of statins in the regulation of HSPs. A better understanding of this involvement can help in development of new and more effective treatment strategies for CVD. [ABSTRACT FROM AUTHOR]

Abstract: Background: To evaluate the relationship between leukocyte‐endothelial cell interactions and oxidative stress parameters in non‐diabetic patients with different grades of obesity. Material and methods: For this cross‐sectional study, 225 subjects were recruited from January 1, 2014 to December 31, 2016 and divided into groups according to BMI (<30 kg/m2, 30‐40 kg/m2 and >40 kg/m²). We determined clinical parameters, systemic inflammatory markers, soluble cellular adhesion molecules, leukocyte‐endothelium cell interactions—rolling flux, velocity and adhesion—, oxidative stress parameters—total ROS, total superoxide, glutathione—and mitochondrial membrane potential in leukocytes. Results: We verified that HOMA‐IR and hsCRP increased progressively as obesity developed, whereas A1c, IL6 and TNFα were augmented in the BMI > 40 kg/m² group. The cellular adhesion molecule sP‐selectin was increased in patients with obesity, while sICAM, total ROS, total superoxide and mitochondrial membrane potential were selectively higher in the BMI > 40 kg/m² group. Obesity induced a progressive decrease in rolling velocity and an enhancement of rolling flux and leukocyte adhesion. Conclusion: Our findings reveal that endothelial dysfunction markers are altered in human obesity and are associated with proinflammatory cytokines and increased oxidative stress parameters. [ABSTRACT FROM AUTHOR]

Objective: Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl ester from HDL-C to LDL-C and VLDL-C. The aim of the present trial was to evaluate the effect of curcumin and its modified formulation on serum CETP concentrations in patients with metabolic syndrome. Materials and Methods: Participants were randomly allocated to one of three groups of 40 subjects receiving either unmodified curcumin or its phospholipid complex or placebo. Lipid profile and plasma CETP were measured at the start and six weeks after initiation of the treatment. The normality of data distribution was assessed by Kolmogorov-Smirnov test. Wilcoxon test was used for comparing the data before and after the intervention. The percent changes of CETP and biochemical factors among the three groups were compared using Kruskal-Wallis test. Results: Serum CETP levels were not significantly altered among patients receiving curcumin. Conclusion: Curcumin and its complex had no significant effect on serum CETP concentrations. [ABSTRACT FROM AUTHOR]

As inflammation had a role in every stage of atherogenesis and hypertension, in turn leading to Cardiovascular Disease. Hs-CRP level estimation can be an important screening method for assessing the risk. Thus, this study to evaluate the effect of essential hypertension on hs- CRP levels in Indian adult population. As well as clustering of other cardiovascular risk factors in comparison with a control group in a population. Acase-control study was carried out in of Era's Lucknow Medical College & Hospital, Lucknow, and Uttar Pradesh. All patients coming in out-patient department were screened for inclusion & exclusion criteria. Those selected were subjected to screening of risk factors of cardiovascular diseases & serum hs CRP estimation. Significant CAD risk factors in our cases came out to be: higher weight (p-value: 0.0470), raised BMI (>25) (p-value: 0.005), higher waist circumference (p-value: 0.0010) & smoking (p-value: 0.008). Average hs-CRP values in the hypertensive group (cases) was higher (2.85 ± 2.4 mg/L) than in normotensive group (control) (2.36 ± 2.08 mg/L). No significant difference in values among the controlled & uncontrolled group of previously diagnosed hypertensives was observed but a significant difference was found between newly diagnosed Stage I & Stage II hypertensives. Also, though not significant a rising trend was noted in hs-CRP values with an increase in the risk category. On CAD risk stratification according to hs CRP values cases hada significantly higher prevalence of hs-CRP levels than controls. Conclusion: The study did not reveal any significant difference in hs CRP values in hypertensives than from the normotensive population. But the significant difference between Stage I & Stage II of hypertension was observed in hs-CRP values. [ABSTRACT FROM AUTHOR]

Human plasma high-density lipoprotein cholesterol concentrations are a negative risk factor for atherosclerosis-linked cardiovascular disease. Pharmacological attempts to reduce atherosclerotic cardiovascular disease by increasing plasma high-density lipoprotein cholesterol have been disappointing so that recent research has shifted from HDL quantity to HDL quality, that is, functional vs dysfunctional HDL. HDL has varying degrees of dysfunction reflected in impaired reverse cholesterol transport (RCT). In the context of atheroprotection, RCT occurs by 2 mechanisms: one is the well-known trans-hepatic pathway comprising macrophage free cholesterol (FC) efflux, which produces early forms of FC-rich nascent HDL (nHDL). Lecithin:cholesterol acyltransferase converts HDL-FC to HDL-cholesteryl ester while converting nHDL from a disc to a mature spherical HDL, which transfers its cholesteryl ester to the hepatic HDL receptor, scavenger receptor B1 for uptake, conversion to bile salts, or transfer to the intestine for excretion. Although widely cited, current evidence suggests that this is a minor pathway and that most HDL-FC and nHDL-FC rapidly transfer directly to the liver independent of lecithin:cholesterol acyltransferase activity. A small fraction of plasma HDL-FC enters the trans-intestinal efflux pathway comprising direct FC transfer to the intestine. SR-B1 −/− mice, which have impaired trans-hepatic FC transport, are characterized by high plasma levels of a dysfunctional FC-rich HDL that increases plasma FC bioavailability in a way that produces whole-body hypercholesterolemia and multiple pathologies. The design of future therapeutic strategies to improve RCT will have to be formulated in the context of these dual RCT mechanisms and the role of FC bioavailability. [ABSTRACT FROM AUTHOR]

The strong relationship between cardiovascular diseases (CVD), atherosclerosis, and endogenous or exogenous lipids has been recognized for decades, underestimating the contribution of other dietary components, such as amino acids, to the initiation of the underlying inflammatory disease. Recently, specific amino acids have been associated with incident cardiovascular disorders, suggesting their significant role in the pathogenesis of CVD. Special attention has been paid to the group of branched-chain amino acids (BCAA), leucine, isoleucine, and valine, since their plasma values are frequently found in high concentrations in individuals with CVD risk. Nevertheless, dietary BCAA, leucine in particular, have been associated with improved indicators of atherosclerosis. Therefore, their potential role in the process of atherogenesis and concomitant CVD development remains unclear. Macrophages play pivotal roles in the development of atherosclerosis. They can accumulate high amounts of circulating lipids, through a process known as macrophage foam cell formation, and initiate the atherogenesis process. We have recently screened for anti- or pro-atherogenic amino acids in the macrophage model system. Our study showed that glycine, cysteine, alanine, leucine, glutamate, and glutamine significantly affected macrophage atherogenicity mainly through modulation of the cellular triglyceride metabolism. The anti-atherogenic properties of glycine and leucine, and the pro-atherogenic effects of glutamine, were also confirmed in vivo. Further investigation is warranted to define the role of these amino acids in atherosclerosis and CVD, which may serve as a basis for the development of anti-atherogenic nutritional and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Microbes such as Chlamydia pneumoniae play an important role in development of atherosclerosis. The bacterium invades vessels walls, directly or indirectly, and by releasing endotoxins or lipopolysaccharides into the bloodstream leads to injuries to endothelial cells. Aim: To determine the prevalence of C. pneumoniae in atherosclerotic plaques of corpses, by PCR (Polymerase Chain Reaction) and to examine the correlation between clinical status and presence of this bacterium in Iran. Materials and Methods: In this descriptive comparative study, a total of 118 samples, including 59 from corpses with atherosclerotic plaques in arteries (44 coronary and 15 abdominal aorta samples) and 59 from corpses without atherosclerotic plaques or obstruct in arteries (44 coronary and 15 abdominal aorta samples) were refrigerated at -70°C. Then, DNA was extracted and to detect C. pneumoniae, the pstI gene was selected and after amplification, samples were electrophoresed to confirm the presence of expected PCR products. The data were analysed using Chi-square statistical test and p-value less than 0.05 was considered to be statistically significant. Also, the relation between C. pneumoniae and some variables of atherosclerotic diseases such as hypertension, hyperlipidemia, smoking and diabetes were studied. Results: In this study, 15% (9/59) of samples from corpses with atherosclerotic plaque were positive for C. pneumoniae DNA, 11% (7/59) in coronary arteries and 4% (2/59) in aortic wall layer while, there was no evidence of C. pneumoniae in corpses with no plaque or obstruction in arteries. Variables such as hypertension, hyperlipidemia and myocardial infarction had higher values in C. pneumoniae positive samples; however, there was no statistically significant difference (p> 0.52). Conclusion: Presence of C. pneumoniae in atherosclerotic plaques and absence in healthy vessels, confirm the possible role of C. pneumoniae in development of atherosclerosis, especially in regions with frequent infections. Nevertheless, the exact mechanism explaining the high prevalence of atherosclerotic vascular disease is completely unknown. [ABSTRACT FROM AUTHOR]

The present review of advances in the treatment of cardiovascular diseases deals with three areas: anti-inflammatory treatment of atherosclerosis, current effect of acetylsalicylic acid, and comparison of strategies for LDL-cholesterol reduction. The first part demonstrates the possibility of anti-inflammatory treatment of atherogenesis with a monoclonal antibody (canakinumab) inactivating interleukin 1β. The effect of inflammation in atherogenesis and thrombogenesis is demonstrated using additional examples - periodontitis or acute viral infection. The current effect of acetylsalicylic acid in women, the elderly, or diabetics has been confirmed based on the data from a Swedish national registry. Termination of treatment resulted in a significant increase in atherothrombotic events, with the increase being more significant when acetylsalicylic acid was indicated as part of secondary prevention. The use of acetylsalicylic acid is supported by an additional antitumour effect (particularly in the prophylaxis of colorectal cancer); this chemoprophylaxis has already been incorporated in the guidelines. The third part involves comparison of the importance of various hypolipidaemic strategies aimed at LDL-cholesterol concentration. Based on a comparison of pharmacotherapy and genetic polymorphisms, it has been shown that of crucial importance is the resulting decline in LDL-cholesterol, not the way it was achieved. [ABSTRACT FROM AUTHOR]

Altered production of reactive oxygen species (ROS), causing lipid peroxidation and DNA damage, contributes to the progression of atherosclerosis and cancer. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a lectin-like receptor for oxidized low-density lipoproteins (ox-LDL) primarily expressed in endothelial cells and vasculature-rich organs. LOX-1 receptors is a marker for atherosclerosis, and once activated by ox-LDL or other ligands, stimulates the expression of adhesion molecules, pro-inflammatory signaling pathways and proangiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. Several different types of cancer reported LOX-1 gene upregulation, and numerous interplays exist concerning LOX-1 in atherosclerosis, metabolic diseases and cancer. One of them involves NF-kB, an oncogenic protein that regulates the transcription of several inflammatory genes response. In a model of cellular transformation, the MCF10A ER-Src, inhibition of LOX-1 gene reduces NF-kB activation and the inflammatory and hypoxia pathways, suggesting a mechanistic connection between cellular transformation and atherosclerosis. The remodeling proteins MMP-2 and MMP-9 have been found increased in angiogenesis in atherosclerotic plaque and also in human prostate cancer cells. In this review, we outlined the role of LOX-1 in atherogenesis and tumorigenesis as a potential link in these diseases, suggesting that LOX-1 inhibition could represent a promising strategy in the treatment of atherosclerosis and tumors. [ABSTRACT FROM AUTHOR]

SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr −/− ) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin −/− Ldlr −/− mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown. Herein we explored the lipodystrophy-related dyslipidemia, steatohepatitis and atherogenesis in another atherosclerosis-prone murine model, apolipoprotein E null (apoE −/− ) mice. Besides, we also compared phenotypes between sexes in apoE −/− mice with Seipin deletion (Seipin −/− apoE −/− ). We found that compared with apoE −/− controls, Seipin −/− apoE −/− mice also developed severe general lipodystrophy with hyperlipidemia, steatohepatitis and increased atherogenesis. Although the severity of adipose loss in female and male Seipin −/− apoE −/− mice were similar, hyperlipidemia, steatohepatitis and atherosclerosis were less severe in females than in males. Therefore, we demonstrated that lipodystrophy-related metabolic disorders, caused by Seipin deletion, were independent of genetic background and experimental diet, as seen in Ldlr −/− and apoE −/− mice. However, gender factor affected the disease progression, with females more resistant to developing lipodystrophy-related metabolic consequences. [ABSTRACT FROM AUTHOR]

Summary: This study was conducted to determine the effects of 8‐week administration of testosterone enanthate (TE) in conjunction with resistance training on thyroid hormones and lipid profiles. Sixty male adult Wistar rats were randomly divided into six groups: C: olive oil, RT: resistance training + olive oil, LD: TE (20 mg/kg), HD: TE (50 mg/kg), RT + LD: RT + TE (20 mg/kg), RT + HD: RT + TE (50 mg/kg). The RT consisted of climbing (5 reps/3 sets) a ladder carrying a load suspended from the tail. At the end, blood specimens were obtained from the orbital sinus and serum concentration of T4, T3, TSH and lipid profiles was determined. The serum concentration of TSH significantly increased in RT + HD group compared to C, and the serum concentration of T4 significantly decreased in LD, HD, RT + LD and RT + HD groups compared to the C and RT groups (p < .05). The concentration of HDL and cholesterol significantly decreased in HD and RT + HD groups compared with C group (p < .05). Both decreased T4 and increased TSH in the RT + HD group likely suggested a primary hypothyroidism as a complication of high‐dose administration of testosterone enanthate along with resistance training. Alteration in lipid profile was another complication observed in rats received high doses of testosterone enanthate. [ABSTRACT FROM AUTHOR]

The "first hit" to atherogenesis is driven by toll-like receptor 4, endoplasmic reticulum stress and ultimately metabolic dysfunction. In this study, we hypothesized that a flaxseed oil-enriched diet (FS) abolishes these inflammatory signaling pathway and restore metabolic homeostasis by activating the fatty acid receptor GPR120 in aorta of obese mice. Glucose homeostasis was assessed by GTT and ITT; lipidomics was performed using a Hybrid Ion Trap-Orbitrap Mass Spectrometer; serum lipids were measured using colorimetric assays; GPR120 and infiltrating macrophages were analyzed by immunofluorescence; protein immunoprecipitation and gene expression were evaluated by Western blot and RT-PCR, respectively. There were no differences in body weight and food intake between the groups from both strains (Swiss and LDLr-KO mice). GTT and cholesterol levels were improved by FS in both mice models. Lipidomics showed an increase in ω3 (C18:3) content, meanwhile stearic acid (C18:0) was not detected in endothelial tissue in response to FS. Moreover, FS markedly decreased pro-inflammatory (IL-1β, TNF-α, pIκBα, pIKKβ) and unfolded protein response markers (ATF6 and GRP78) in aorta. In Swiss mice, GPR120 was partially involved in the ω3-mediated anti-inflammatory actions, disrupting TLR4 pathway, but not in LDLr-KO mice. Partial replacement of dietary saturated by unsaturated ω3 fatty acids contributes to inhibition of cardiovascular risk markers, pro-inflammatory cytokines and ER stress sensors and effectors in the aorta. However, downregulation of inflammation is not mediated by arterial GPR120 activation. [ABSTRACT FROM AUTHOR]

Abstract: Endothelial inflammatory responses promote the development and progression of atherosclerosis. It was reported that Toll‐like receptors 2 (TLR2) is associated with endothelial inflammation. However, the effect of TLR2 on inflammatory responses in human coronary artery endothelial cells (HCAECs) remains largely unknown. Here, we tested the hypothesis that TLR2 can enhance inflammatory reactions in HCAECs after stimulated by TLR2 agonist. First, we used CRISPR‐Cas9 technology to knockout TLR2 gene in HCAECs. Then, TLR2‐KO and wild type HCAECs were treated with TLR2 agonist peptidoglycan (PGN). The expression levels of intercellular cell adhesion molecule‐1 (ICAM‐1), interleukin‐6 (IL‐6), and interleukin‐8 (IL‐8) were analyzed by real‐time PCR, Western blot, and ELISA. The expression status of myeloid differentiation primary response gene 88 (MyD88), phosphorylated IRAK‐1 (pIRAK‐1) and phosphorylated NF‐κB (pNF‐κB) were detected by Western blot. Our results show that after treated with TLR2 agonist, the expression levels of ICAM‐1, IL‐6, and IL‐8 were downregulated in TLR2‐KO cells compared to those of wild type cells. Further, Western blots of MyD88, pIRAK‐1, and pNF‐κB show that the expression levels of these pro‐inflammatory molecules were much lower in TLR2‐KO cells compared to that of wild type cells by stimulating with TLR2 agonist. We suggest that TLR2 may affect inflammatory reaction in HCAECs by introducing pro‐inflammatory molecules like MyD88, pIRAK‐1, and pNF‐κB. [ABSTRACT FROM AUTHOR]

BackgroundGenome‐wide association studies identified ADAMTS7 as a risk locus for coronary artery disease (CAD). Functional studies suggest that ADAMTS7 may promote cellular processes in atherosclerosis. We sought to examine the association between genetic variation at ADAMTS7 and measures of atherosclerosis using histological, angiographic, and clinical outcomes data. Methods and ResultsThe lead CAD‐associated single‐nucleotide polymorphism rs3825807 at the ADAMTS7 locus was genotyped. The G allele (reduced ADAMTS7 function) was associated with a smaller fibrous cap (P=0.017) and a smaller percentage area of α‐actin (smooth muscle cell marker) in the intima (P=0.017), but was not associated with calcification or plaque thickness, following ex vivo immunohistochemistry analysis of human coronary plaques (n=50; mean age 72.2±11.3). In two independent cohorts (Southampton Atherosclerosis Study [n=1359; mean age 62.5±10.3; 70.1% men] and the Emory Cardiovascular Biobank [EmCAB; n=2684; mean age 63.8±11.3; 68.7% men]), the G allele was associated with 16% to 19% lower odds of obstructive CAD (Southampton Atherosclerosis Study: odds ratio, 0.81; 95% confidence interval, 0.67–0.98; EmCAB: odds ratio, 0.84; 95% confidence interval, 0.75–0.95) with similar effects for multivessel, left anterior descending, and proximal CAD. Furthermore, each copy of the G allele was associated with lower angiographic severity Gensini score (Southampton Atherosclerosis Study, P=0.026; EmCAB, P

The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Here we characterize a novel LXR target gene, the lipopolysaccharide binding protein (LBP) gene. Surprisingly, the ability of LXRs to control LBP expression is cell-type specific, occurring in macrophages but not liver. Treatment of macrophages with oxysterols or loading with modified LDL induces LBP in an LXR-dependent manner, suggesting a potential role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies. After 18 weeks of Western diet feeding, atherosclerotic lesion burden was assessed revealing markedly smaller lesions in the LBP−/− recipients. Furthermore, loss of bone marrow LBP expression increased apoptosis in atherosclerotic lesions as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Supporting in vitro studies with isolated macrophages showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. The LBP gene is a macrophage-specific LXR target that promotes foam cell survival and atherogenesis.

Atherosclerosis has long been known to be a chronic inflammatory disease. In addition, there is intense oxidative stress in atherosclerosis resulting from an imbalance between the excess reactive oxygen species (ROS) generation and inadequate anti-oxidant defense forces. The excess of the oxidative forces results in the conversion of low-density lipoproteins (LDL) to oxidized LDL (ox-LDL), which is highly atherogenic. The sub-endothelial deposition of ox-LDL, formation of foamy macrophages, vascular smooth muscle cell (VSMC) proliferation and migration, and deposition of collagen are central pathophysiologic steps in the formation of atherosclerotic plaque. Ox-LDL exerts its action through several different scavenger receptors, the most important of which is LOX-1 in atherogenesis. LOX-1 is a transmembrane glycoprotein that binds to and internalizes ox-LDL. This interaction results in variable downstream effects based on the cell type. In endothelial cells, there is an increased expression of cellular adhesion molecules, resulting in the increased attachment and migration of inflammatory cells to intima, followed by their differentiation into macrophages. There is also a worsening endothelial dysfunction due to the increased production of vasoconstrictors, increased ROS, and depletion of endothelial nitric oxide (NO). In the macrophages and VSMCs, ox-LDL causes further upregulation of the LOX-1 gene, modulation of calpains, macrophage migration, VSMC proliferation and foam cell formation. Soluble LOX-1 (sLOX-1), a fragment of the main LOX-1 molecule, is being investigated as a diagnostic marker because it has been shown to be present in increased quantities in patients with hypertension, diabetes, metabolic syndrome and coronary artery disease. LOX-1 gene deletion in mice and anti-LOX-1 therapy has been shown to decrease inflammation, oxidative stress and atherosclerosis. LOX-1 deletion also results in damage from ischemia, making LOX-1 a promising target of therapy for atherosclerosis and related disorders. In this article we focus on the different mechanisms for regulation, signaling and the various effects of LOX-1 in contributing to atherosclerosis.