Development Of Early Atherosclerotic Lesions Research Articles

Treatment with APAC, a dual antiplatelet anticoagulant heparin proteoglycan mimetic, limits early collar-induced carotid atherosclerotic plaque development in Apoe−/− mice

Background and aimsMast cell-derived heparin proteoglycans (HEP-PG) can be mimicked by bioconjugates carrying antithrombotic and anti-inflammatory properties. The dual antiplatelet and anticoagulant (APAC) construct administered, either locally or intravenously (i.v.), targets activated endothelium, its adhesion molecules, and subendothelial matrix proteins, all relevant to atherogenesis. We hypothesized that APAC influences cellular interactions in atherosclerotic lesion development and studied APAC treatment during the initiation and progression of experimental atherosclerosis. MethodsMale western-type diet-fed Apoe−/− mice were equipped with perivascular carotid artery collars to induce local atherosclerosis. In this model, mRNA expression of adhesion molecules including ICAM-1, VCAM-1, P-Selectin, and Platelet Factor 4 (PF4) are upregulated upon lesion development. From day 1 (prevention) or from 2.5 weeks after lesion initiation (treatment), mice were administered 0.2 mg/kg APAC i.v. or control vehicle three times weekly for 2.5 weeks. At week 5 after collar placement, mice were sacrificed, and lesion morphology was microscopically assessed. ResultsAPAC treatment did not affect body weight or plasma total cholesterol levels during the experiments. In the prevention setting, APAC reduced carotid artery plaque size and volume by over 50 %, aligning with decreased plaque macrophage area and collagen content. During the treatment setting, APAC reduced macrophage accumulation and necrotic core content, and improved markers of plaque stability. ConclusionsAPAC effectively reduced early atherosclerotic lesion development and improved markers of plaque inflammation in advanced atherosclerosis. Thus, APAC may have potential to alleviate the progression of atherosclerosis.

Коморбідний пацієнт: міждисциплінарна проблема (огляд літератури)

The comorbidity of arterial hypertension (AH), type 2 diabetes mellitus (T2DM), obesity leads to the early development of atherosclerotic lesions of coronary and cerebral vessels, which, in turn, significantly accelerates the occurrence of coronary arterial disease (CHD), vascular disasters, namely, myocardial infarction (MI), stroke. Comorbidity fully refers to the concept of “metabolic syndrome”. By definition, metabolic syndrome (MS) is a complex of interrelated clinical, metabolic and hormonal disorders caused by the dysregulation of various genes, the influence of external environmental factors, associated with increased cardiovascular risk, and an increase in overall mortality. The article is intended to review modern scientific literature on metabolic syndrome and comorbid conditions associated with it.

Zerumbone ameliorates the induced atherosclerosis-initiated inflammatory conditions through suppression of proinflammatory mediators and inflammatory cytokines

Background: Zerumbone (ZER) is a naturally occurring monosesquiterpine and dietary compound from Zingiber zerumbet Smith, an edible ginger. It has been shown to possess anti-inflammatory activities. Inflammation plays an important role in all stages of atherosclerosis. However, little is known about ZER's anti-inflammatory role in atherosclerosis. Objectives: This study investigated the anti-inflammatory effect of ZER in mitigating the formation and development of early atherosclerotic lesions in rabbits fed with high-cholesterol diet. Materials and Methods: A total of 72 New Zealand White rabbits were used in two experimental studies carried out at different times. The first experiment was carried out to investigate the prophylactic effects of ZER in preventing premature atheromas plaque formation. In contrast, the second experiment was carried out to assess the therapeutic efficacy of ZER in reducing atheromas lesion progression and dissemination. Results: ZER significantly (P

Взаємозв’язок активності матриксної металопротеїнази-2 та -9 в гомогенаті міокарда зі змінами клітинного складу стінки вінцевих артерій в експерименті

Matrix metalloproteinases are involved in a complex multifactorial process of atherosclerotic plaque formation and play a leading role in the degradation of the extracellular matrix components and increase the migratory activity of cellular elements of the vascular wall. Despite a number of scientific studies, it is necessary to identify clear biochemical markers for the development of atherosclerotic lesions. The purpose of the study was to investigate the relationship between the activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 in myocardial homogenate with changes of the cells composition in the coronary arteries wall in experimental atherosclerosis. Materials and methods. The studies were performed on 76 nonlinear rats, which were divided into 3 groups: group Ia was the control (n=20) – animals, injected intracutaneously with 0.1 ml of 0.9 % sodium chloride solution; Ib – comparison group (n=20) – animals injected with incomplete Freund’s adjuvant at the dose of 0.1 ml intracutaneously and II – experimental group (n=36), which were immunized with native human low-density lipoprotein at a single dose of 200 μg, diluted in 0.1 ml of incomplete Freund’s adjuvant, regardless of the weight. The experiment lasted for 20 weeks. Material sampling was performed, starting from the 4th week after the drug administration. From the coronary arteries and the adjacent myocardium, microslides were made according to the generally accepted technique, which were stained with hematoxylin and eosin, according to the methods of Van Gizon, Mallory and Sudan III. The activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 was determined by enzyme-zimografic method. Results and discussion. The growth of matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in atherosclerotic lesions showed stages of degradation of extracellular matrix components: the dynamics of matrix metalloproteinase-2 activity during the experiment increased from 109.1±1.23 % at the 12th week to 127.32±0.99 % at the 20th week. The increased activity of matrix metalloproteinase-2 was associated with an increase in the number of leukocytes and macrophages, including foam cells. The activity of matrix metalloproteinase-9 reached the highest values of 98.24±0.82% at the 8th period from the onset of changes to the final level of 86.26±0.54% at the maximum terms of the experiment. Conclusion. The growing activity of matrix metalloproteinase-9 indicated the development of early atherosclerotic lesions, while the high level of activity of matrix metalloproteinase-2 indicated significant structural changes in the wall of the coronary arteries

Prediction of atherosclerosis diseases using biosensor-assisted deep learning artificial neuron model

In the present medical era, the major cause of the rise in death rate worldwide is atherosclerosis disease and this diagnosis is complicated because initial signs are unattended. To reduce the costs of treatment and prevent serious events, it is necessary to improve the prediction accuracy of cardiovascular diseases during plaque formation. This proposal is intended to create a support system for the biosensor-assisted deep learning concepts for detecting atherosclerosis disease. With the clinical data, this mathematical model can predict heart disease based on deep learning-assisted k-means geometric distribution artificial neuron model. The atherosclerotic plaque formation mathematical model explains the early atherosclerotic lesion development in a more accurate manner. Further, the creation of the atherosclerotic plate, the test performs numerical simulations with idealized two-dimensional carotid artery bifurcation geometry. The proposed system has been analyzed using a variety of similarity tests such as the coefficient Matthews’s correlation (CMC). Furthermore, the results have reached 95.66% accuracy and 0.93 CMC, which are significantly higher than published conventional research.

Cardiovascular Effects of Cyclical Dietary Vitamin C Withdrawal in Mice Deficient in Internal Synthesis Vitamin C and producing human lipoprotein (a): Gulo(-/-); Lp(a)+

Background: Scientific knowledge of the impact of periodic dietary vitamin C intake and withdrawal on the development of cardiovascular disease has been limited. Our earlier study using a transgenic Gulo(-/-); Lp(a)+ mouse model mimicking human metabolism in respect to a lack of internal synthesis of vitamin C and expression of human lipoprotein (a) [Lp(a)], a recognized risk factor for cardiovascular disease, showed that vitamin C deficiency triggers vascular deposition of Lp(a) and atherosclerosis. In this study we used this mouse model to investigate the effect of cyclical vitamin C withdrawal and its continuous supplementation on metabolic factors related to cardiovascular health, such as lipid profile and vascular plaque development. Methods: Gulo (-/-); Lp (a)+ mice were subjected to 4 weeks of dietary vitamin C withdrawals followed by 4 weeks of a resupplementation pattern for 20 weeks in total. Mice supplemented with vitamin C continuously for 20 weeks served as reference control. Mice were harvested after 4, 8, 12, 16, and 20 weeks and analyzed. Serum ascorbic acid, lipid profile, lipoproteins, vascular lesion, and Lp(a) deposition were evaluated. Results: We observed that periodic vitamin C withdrawals resulted in a less healthy blood lipid profile and showed indications of metabolic adaptation to vitamin C withdrawals. In addition, mice experiencing recurring dietary vitamin C withdrawals were prone to the development of early atherosclerotic lesions with Lp(a) deposition in the structurally compromised areas of the vascular wall, compared to mice continuously supplemented with vitamin C. Conclusion: This study further supports the importance of consistent and sufficient intake of vitamin C in assuring optimum profile of blood risk factors, and maintaining vascular wall integrity and optimal cardiovascular health.

Premature Reflection of Type IIa Hyperlipoproteinemia in the Peripheral Arteries

Hyperlipoproteinemia may lead to early development of atherosclerosis especially when present in familial forms. Serum low-density lipoprotein (LDL) cholesterol is known to be the most important form of atherosclerotic particules. Type IIa hyper-lipoproteinemia is one of the most important form of these familial disorders and gives rise to extremely elevated serum LDL cholesterol levels. Beside the cardiovascular mortality risk that the patient carries because of the early development of atherosclerotic lesions in all vascular tree, this clinical entity also manifests itself with accumulation of cholesterol particules on the skin. Herein we report a very early presentation of Type IIa hyperlipoproteinemia with both atherosclerotic lesions in the arteries and lipid deposites on the skin.

Cholesterol screening and statin use in children: a literature review.

Atherosclerosis begins in childhood. Fatty streaks, the earliest precursor of atherosclerotic lesions, have been found in the coronary arteries of children of 2years of age. Hypercholesterolaemia is a risk factor for coronary artery disease. Hypercholesterolaemia can be either primary, when it is characteristic of the main disease, or secondary when it occurs as a result of either a disease process or drug treatment. Given the risk of vascular disease, including myocardial infarction (MI), cerebrovascular accidents (CVA, also known as strokes), peripheral vascular disease (PVD) and ruptured aortic aneurysm, which may follow atherosclerosis, it is important to prevent or slow the early development of atherosclerotic lesions. This prevention necessitates the control of key risk factors such hypercholesterolaemia, dyslipidaemia, hypertension etc. However, at what point this prevention ought to occur, and in what form, is uncertain. Using pharmacological primary prevention for hypercholesterolaemia in the paediatric population is controversial. In an adult patient, hypercholesterolaemia warrants the initiation of a statin. Statins, also known as hydroxymethylglutaryl co-enzyme A inhibitors (or HMG-CoA inhibitors) act by altering cholesterol metabolism. In the paediatric population, the clinical course of vascular disease and the effect of altering this clinical course are less certain. This article reviews the published literature on hypercholesterolaemia in children and the use of statins as a treatment for dyslipidaemia in children. The US National Cholesterol Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 2012 guidelines (NCEP guidelines) regarding the recognition and treatment of childhood dyslipidaemia are reviewed.

An exploratory factor analysis of inflammatory and coagulation markers associated with femoral artery atherosclerosis in the San Diego Population Study

Background and aimsSeveral biomarkers of inflammation and coagulation have been implicated in lower extremity atherosclerosis. We utilized an exploratory factor analysis (EFA) to identify distinct factors derived from circulating inflammatory and coagulation biomarkers then examined the associations of these factors with measures of lower extremity subclinical atherosclerosis, including the ankle-brachial index (ABI), common and superficial femoral intima-media thickness (IMT), and atherosclerotic plaque presence, burden, and characteristics. MethodsThe San Diego Population Study (SDPS) is a prospective, community-living, multi-ethnic cohort of 1103 men and women averaged age 70. Regression analysis was used to assess cross-sectional associations between the identified groupings of biomarkers (factors) and the ABI and femoral artery atherosclerosis measurements. ResultsTwo biomarker factors emerged from the factor analysis. Factor 1 consisting of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen was significantly associated with higher odds (OR = 1.99, p < 0.01) of a borderline ABI value (0.91–0.99), while Factor 2 containing D-dimer and pentraxin (PTX)-3 was significantly associated with higher common femoral artery (CFA) IMT (β = 0.23, p < 0.01) and lower ABI (β = −0.03, p < 0.01). ConclusionsTwo groupings of biomarkers were identified via EFA of seven circulating biomarkers of inflammation and coagulation. These distinct groups are differentially associated with markers of lower extremity subclinical atherosclerosis. Our findings suggest that high inflammatory and coagulation burden were better markers of more severe lower-extremity disease as indicated by low ABI rather than early atherosclerotic lesion development in the femoral artery.

JAK2V617F Promotes Atherosclerosis

Myeloproliferative disorder (MPD) patients are at high risk of atherothrombotic events including myocardial infarction and stroke. The somatic mutation (JAK2V617F) is commonly found in MPD patients and is associated with increased vascular risk. Moreover, the prevalence of JAK2V617F mutation is also significantly increased in non-MPD coronary artery disease (CAD) and peripheral artery disease (PAD) patients compared to the general population. Our goal was to investigate potential mechanisms of accelerated atherothrombosis using a JAK2V617F mouse model.Subletahlly irradiated Ldlr-/- mice were transplanted with bone marrow cells from wild type (WT) or Mx1-Cre/Jak2V617F (Jak2VF) mice and fed a high fat high cholesterol Western type diet (WTD). After 7 weeks of WTD Jak2VFmice had sustained neutrophilia, monocytosis and erythrocytosis; despite lower plasma cholesterol levels they showed ~1.6 fold larger atherosclerotic lesions in the aortic root (p=0.003) and accelerated carotid artery thrombosis (FeCl3 injury). After 12 weeks of WTD feeding, lesion area was only increased 1.3-fold compared to controls but showed features of plaque instability (increased necrotic core area). Early lesions (7 weeks) displayed significantly increased neutrophils (p=0.05, n=7) but not Mac 3+ macrophages. The increased neutrophil infiltration in Jak2VF mice correlated with atherosclerotic lesion size (p=0.001, r=0.78), suggesting a critical role of neutrophils in early atherogenesis. Advanced lesions (12 weeks) also showed significantly increased neutrophil (p=0.001) and macrophage (p=0.05) infiltration. No difference in CD3+ T cells or CD41+ platelet infiltration was observed at either time-point. In addition, five out of nine Jak2VF mice had prominent iron deposition (Prussian blue) and RBC marker Ter-119 staining in advanced atherosclerotic lesions (p<0.05). RBC marker Ter-119 co-localized with Mac-3(+) macrophages surrounding necrotic cores, indicating erythrophagocytosis and plaque instability.In summary, the Jak2V617F mutation promotes early atherosclerotic lesion development and plaque instability in advanced lesions. Neutrophil infiltration appears to be an important contributor to both early lesion development and necrotic core formation. These studies also suggest a novel role for RBC infiltration, iron deposition and erythrophagocytosis in advanced lesional necrotic core formation in JAK2V617F mice. DisclosuresLevine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Tall:Amgen: Consultancy; CSL Behring: Consultancy.

Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro

The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) plays a crucial role in the initiation of atherosclerosis. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important molecules involved in the adhesion of monocytes to HUVECs. Previous studies have suggested that artemisinin, apart from an anti-malarial agent, also has other effects. In the present study, we found that artemisinin significantly decreased the adhesion of monocytes to tumor necrosis factor-α (TNF-α)-stimulated HUVECs in a dose-dependent manner and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in the TNF-α-stimulated HUVECs. In addition, the nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, and mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and U0126) respectively reduced the adhesion of monocytes to TNF-α-stimulated HUVECs, and suppressed ICAM-1 and VCAM-1 expression in TNF-α stimulated HUVECs. Moreover, artemisinin impeded the activation of the NF-κB and MAPK signaling pathways. Furthermore, Bay 11-7082 significantly decreased the phosphorylation of levels extracellular signal-regulated protein kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK). Taken together, the findings of our study indicated that artemisinin blocked monocyte adhesion to TNF-α-stimulated to HUVECs by downregulating ICAM-1 and VCAM-1 expression in the TNF-α-stimulated HUVECs. Artemisinin may thus have potential for use in the protection against the early development of atherosclerotic lesions.

Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy.

Preeclampsia (PE), gestational diabetes mellitus (GDM), and maternal supraphysiological hypercholesterolaemia (MSPH) are pregnancy-related conditions that cause metabolic disruptions leading to alterations of the mother, fetus and neonate health. These syndromes result in fetoplacental vascular dysfunction, where nitric oxide (NO) plays a crucial role. PE characterizes by abnormal increase in the placental blood pressure and a negative correlation between NO level and fetal weight, suggesting that increased NO level and oxidative stress could be involved. GDM courses with macrosomia along with altered function of the fetal cardiovascular system and fetoplacental vasculature. Even when NO synthesis in the fetoplacental vasculature is increased, NO bioavailability is reduced due to the higher oxidative stress seen in this disease. In MSPH, there is an early development of atherosclerotic lesions in fetal and newborn arteries, altered function of the fetoplacental vasculature, and higher markers of oxidative stress in fetal blood and placenta, thus, vascular alterations related with NO metabolism occur as a consequence of this syndrome. Potential mechanisms of altered NO synthesis and bioavailability result from transcriptional and post-translational NO synthases (NOS) modulation, including phosphorylation/dephosphorylation cycles, coupling/uncoupling of NOS, tetrahydrobiopterin bioavailability, calcium/calmodulin-NOS and caveolin-1-NOS interaction. Additionally, oxidative stress also plays a role in the reduced NO bioavailability. This review summarizes the available information regarding lower NO bioavailability in these pregnancy pathologies. A common NO-dependent mechanism in PE, GDM and MSPH contributing to fetoplacental endothelial dysfunction is described.

The Antiatherogenic Effect of Fish Oil in Male Mice Is Associated with a Diminished Release of Endothelial ADAM17 and ADAM10 Substrates1–3

Background: Growing evidence suggests that disintegrin and metalloprotease (ADAM) 17 (ADAM17) and ADAM10 contribute to the pathogenesis of vascular diseases. ADAM17 promotes inflammatory processes by liberating tumor necrosis factor α, interleukin 6 receptor (IL-6R), and tumor necrosis factor receptor 1 (TNFR1). ADAM17 and ADAM10 modulate vascular permeability by cleaving endothelial adhesion molecules such as junctional adhesion molecule A (JAM-A) and vascular endothelial cadherin (VE-cadherin), respectively.Objective: This study was designed to investigate whether a link might exist between the protective effects of fish oil (FO) supplementation against atherosclerosis and ADAM functionMethods: Male LDL receptor knockout (LDLR−/−) mice and male wild-type (WT) mice were fed a Western diet (200 g/kg fat, 1.5 g/kg cholesterol) containing either 20% lard (LDLR−/−-lard and WT-lard groups) or 10% lard combined with 10% FO (LDLR−/−-FO and WT-FO groups) for 12 wk. Atherosclerotic lesion development and fatty acid composition of liver microsomes were evaluated. ADAM10 and ADAM17 expression was determined by quantitative real-time polymerase chain reaction and immunoblot analyses. Concentrations of soluble ADAM substrates in plasma and liver extracts were measured by ELISAResults: Diets supplemented with FO markedly reduced development of early atherosclerotic lesions in LDLR−/− mice (LDLR−/−-lard group vs. LDLR−/−-FO group mean ± SD: 29.6 ± 6.1% vs. 22.5 ± 4.2%, P < 0.05). This was not accompanied by changes in expression of ADAM17 or ADAM10 in the aorta or liver. No dietary effects on circulating TNFR1 (LDLR−/−-lard group vs. LDLR−/−-FO group mean ± SD: 1.22 ± 0.23 vs. 1.39 ± 0.28, P > 0.2) or IL-6R (1.06 ± 0.12 vs. 0.98 ± 0.09 fold of WT-lard group, P > 0.1), classical substrates of ADAM17 on macrophages, and neutrophil granulocytes were observed. However, a reduction in atherosclerotic lesions in the LDLR−/−-FO group was accompanied by a significant reduction in the circulating endothelial cell adhesion molecules JAM-A (LDLR−/−-lard group vs. LDLR−/−-FO group mean ± SD: 1.42 ± 0.20 vs. 0.95 ± 0.56 fold of WT-lard group, P < 0.05), intercellular adhesion molecule 1 (1.15 ± 0.14 vs. 0.88 ± 0.17 fold of WT-lard group, P < 0.05), and VE-cadherin (0.88 ± 0.12 vs. 0.72 ± 0.15 fold of WT-lard group, P < 0.05), reflecting reduced ADAM activity in endothelial cellsConclusion: FO exerted an antiatherogenic effect on male LDLR−/− mice that was accompanied by a reduced release of ADAM17 and ADAM10 substrates from endothelial cells. It is suggested that FO-decreased ADAM activity contributes to improved endothelial barrier function and thus counteracts intimal lipoprotein insudation and macrophage accumulation.

Modulation of platelet and monocyte function by the chemokine fractalkine (CX3 CL1) in cardiovascular disease.

The chemokine fractalkine, CX3CL1, bears unique features within the chemokine family: it exists in a membrane bound form acting as an adhesion molecule and surface receptor; however, when cleaved by ADAM 10, it functions as a soluble chemokine. Fractalkine and its chemokine receptor CX3CR1 are known to have multiple roles in diverse human diseases, for example inflammatory diseases, rheumatoid arthritis, renal diseases and atherosclerosis. This review is based on the material obtained via PubMed up to November 2014. The key search terms used were 'fractalkine', 'CX3CL1', 'CX3CR1', 'cardiovascular disease', 'platelets', 'monocytes' and 'platelet-monocyte complexes'. Atherosclerosis is recognized as a highly inflammatory disease, and it has become increasingly evident that the immune system plays an important role in atherogenesis and atheroprogression. Two blood cell populations are crucially involved in the early development of atherosclerotic lesions: monocytes and platelets. They are detected at vascular sites of endothelial dysfunction and are involved in inflammatory immune responses. These cells directly interact with each other, forming platelet-monocyte complexes that are increased in cardiovascular diseases. During the development of atherosclerosis, fractalkine mediates leukocyte recruitment to the inflamed endothelium, which promotes early formation of lesions. This process only effectively works in the presence of activated platelets. It has been suggested that fractalkine and its receptor contribute to platelet-monocyte aggregate formation underlining the two important impacts of this chemokine for platelets as well as monocytes. Interesting data hint at a role of fractalkine for platelet activation, adhesion and subsequent monocyte recruitment to activated endothelial cells in cardiovascular diseases. However, the exact mechanisms remain to become unravelled.

Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2.

Macrophage survival is believed to be a contributing factor in the development of early atherosclerotic lesions. Dysregulated apoptosis of macrophages is involved in the inflammatory process of atherogenesis. Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-inflammatory, antiplatelet, and antitumor activities. Here we showed that apigenin attenuated atherogenesis in apoE −/− mice in an in vivo test. In vitro experiments suggested that apigenin induced apoptosis of oxidized low density lipoprotein- (OxLDL-) loaded murine peritoneal macrophages (MPMs). Proteomic analysis showed that apigenin reduced the expression of plasminogen activator inhibitor 2 (PAI-2). PAI-2 has antiapoptotic effects in OxLDL-loaded MPMs. Enhancing PAI-2 expression significantly reduced the proapoptosis effects of apigenin. Molecular docking assay with AutoDock software predicted that residue Ser473 of Akt1 is a potential binding site for apigenin. Lentiviral-mediated overexpression of Akt1 wild type weakened the proapoptosis effect of apigenin in OxLDL-loaded MPMs. Collectively, apigenin executes its anti-atherogenic effects through inducing OxLDL-loaded MPMs apoptosis. The proapoptotic effects of apigenin were at least partly attributed to downregulation of PAI-2 through suppressing phosphorylation of AKT at Ser473.

Clinical and biochemical predictors of carotid intima media thickness in adolescents with type 2 diabetes

The aim of this study was to identify clinical parameters associated with increased carotid intima media thickness (CIMT) in adolescents with type 2 diabetes. Overweight children and adolescents are at increased risk of type 2 diabetes and early development of atherosclerotic lesions and cardiovascular complications. Patients were selected among diabetics who presented to diabetes out patients’ clinic. Criteria for selection were age (12–19 years), being overweight (BMI above the 95th percentile for age and gender), normal or high C-peptide, and negative studies for islet cell antibodies. Age and gender matched healthy subjects, were enrolled as a control group. Laboratory investigations included lipid profile, hypersensitive C-reactive protein (hs-CRP), HbA1c and assessment of insulin resistance by HOMA. According to HbA1c, patients were divided into, uncontrolled group (with HbA1c >6.5) and controlled group (with HbA1c ⩽ 6.5). Ultrasonographic analysis of CIMT was performed for all participants and its association with risk variables was analyzed. BMI, triglycerides, C-reactive protein, HbA1c and HOMA were significantly higher in diabetic patients than the controls. CIMT, HbA1c, systolic blood pressure, triglycerides, HOMA and C-reactive protein were significantly higher in uncontrolled than controlled diabetics, while there was no significant difference between the two groups as regard BMI, total cholesterol, LDL, HDL and C-peptide. In diabetic patients, CIMT correlated positively with BMI, duration of diabetes, systolic and diastolic blood pressure, HbA1c, HOMA, and C reactive protein. CIMT is increased in adolescents with type 2 diabetes as compared to control subjects. Poor glycemic control, HOMA, increased C reactive protein, BMI, duration of diabetes and elevated blood pressure are associated with early atherosclerosis in these patients.

Immunization With a Combination of 2 Peptides Derived From the C5a Receptor Significantly Reduces Early Atherosclerotic Lesion in Ldlr tm1Her Apob tm2Sgy J Mice

The goal of this study was to assess whether immunization of Ldlr(tm1Her) Apob(tm2Sgy) J mice with 2 peptides located at the N-terminus of the C5a receptor (C5aR), either alone or in combination, is effective in reducing atherosclerotic lesions. Five- to 6-week-old female Ldlr(tm1Her)Apob(tm2Sgy) J mice were immunized using a repetitive immunization multiple sites strategy with keyhole limpet hemocyanin-conjugated peptides derived from the C5aR, either alone (designated as C5aR-P1 [aa 1-21] and C5aR-P2 [aa 19-31]) or in combination (designated as C5aR-P1+C5aR-P2). Mice were fed a high-fat diet for 10 weeks. Lesions were evaluated histologically; local and systemic immune responses were analyzed by immunohistochemistry of aorta samples and cytokine measurements in plasma samples and splenocyte supernatants. Immunization of Ldlr(tm1Her)Apob(tm2Sgy) J mice with these peptides elicited high concentrations of antibodies against each peptide. Immunization with the single peptide inhibited plaque development. Combined inoculation with C5aR-P1+C5aR-P2 had an additive effect on reducing the lesion in the aorta sinus and descending aortas when compared with controls. This effect correlated with cellular infiltration and cytokine/chemokine secretion in the serum or in stimulated spleen cells as well as specific cellular immune responses when compared with controls. Immunization of mice with C5aR-P1 and C5aR-P2, either alone or in combination, was effective in reducing early atherosclerotic lesion development. The combined peptide is more potential than either epitope alone to reduce atherosclerotic lesion formation through the induction of a specific Treg cell response as well as blockage of monocyte differentiation into macrophages.

YIA 1 Toll-like receptor 3 expression is increased in atherosclerosis and confers protection against early atherosclerotic lesion development and weight gain in apolipoprotein E deficient mice

IntroductionPrevious studies have assigned detrimental roles to toll-like receptors (TLR) in cardiovascular disease. Recently we described a novel protective role for TLR3 in vivo in intimal hyperplasia.AimUsing human and murine...

Hematopoietic Fas Deficiency Does Not Affect Experimental Atherosclerotic Lesion Formation despite Inducing a Proatherogenic State

The Fas death receptor (CD95) is expressed on macrophages, smooth muscle cells, and T cells within atherosclerotic lesions. Given the dual roles of Fas in both apoptotic and nonapoptotic signaling, the aim of the present study was to test the effect of hematopoietic Fas deficiency on experimental atherosclerosis in low-density lipoprotein receptor-null mice (Ldlr(-/-)). Bone marrow from Fas(-/-) mice was used to reconstitute irradiated Ldlr(-/-) mice as a model for atherosclerosis. After 16 weeks on an 0.5% cholesterol diet, no differences were noted in brachiocephalic artery lesion size, cellularity, or vessel wall apoptosis. However, Ldlr(-/-) mice reconstituted with Fas(-/-) hematopoietic cells had elevated hyperlipidemia [80% increase, relative to wild-type (WT) controls; P < 0.001] and showed marked elevation of plasma levels of CXCL1/KC, CCL2/MCP-1, IL-6, IL-10, IL-12 subunit p70, and soluble Fas ligand (P < 0.01), as well as systemic microvascular inflammation. It was not possible to assess later stages of atherosclerosis because of increased mortality in Fas(-/-) bone marrow recipients. Our data indicate that hematopoietic Fas deficiency does not affect early atherosclerotic lesion development in Ldlr(-/-) mice.

BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A 2 (TXA 2) and 8-iso-PGF 2α have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB 2 synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF 2α. Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E −/− mice than sole inhibition of TXA 2 formation.