Early Development Of Atherosclerosis Research Articles

#331 Vascular and lipid profile interplays in pediatric CKD patients

Abstract Background and Aims Chronic kidney disease (CKD) is characterized by irreversible kidney damage and/or progressive loss of function. Children with CKD often have additional CVD risk factors, including hypertension and dyslipidemia. They may have myocardial abnormalities and early atherosclerosis evidence, such as coronary artery calcification, abnormal flow-mediated dilation, increased carotid intima-medial thickness (CIMT), and increased aortic stiffness. These abnormalities seem to be, in part, related to the degree of uremia. This study aimed at assessing the interrelationship between vascular status and lipid profile abnormalities in different stages of CKD in pediatric patients. Method This cross-sectional study was done on 99 patients: 33 with stage 5 CKD on regular hemodialysis & 33 pre-dialysis CKD stage 2-4 on conservative management & 33 age and sex matched controls. Anthropometric measures, blood pressure readings, and a lipid profile were done to all groups. Intima media thickness was measured using B-mode ultrasound doppler in both the common and internal carotid arteries (CCA, ICA). Which is a non-invasive way to measure the artery walls and track the early impacts of the atherosclerotic process. Results There was an obvious increase in blood pressure the percentiles in all CKD patients in relation to controls. The waist-to-hip ratio in CKD 2-4 patients was significantly higher than in CKD 5 patients, and both were higher than the controls, with means (±SD) of 1.01 (0.19), 0.88 (0.10), and 0.86 (0.05), respectively. Except for high-density lipoproteins (HDL), the lipid profile, including triglycerides, cholesterol, and low-density lipoproteins (LDL), were all significantly increased when comparing CKD 2-4 to CKD 5, and both higher than the controls: 170.45 (42.04), 166.00 (45.57), and 100.88 (26.19) for triglycerides (p 0.001). The right and left ICA and CCA showed a significant increase in the intimal thickness being higher in the CKD 5 group than the CKD 2-4 and both higher than the controls. On studying the correlation between the duration of CKD in years and other variables, we found a positive correlation with triglycerides (r = 0.409 & p = 0.001) and right CCA IMT (r = 0.271 & p = 0.028); however, the HDL (r = −0.326 & p = 0.007) revealed a negative correlation in all CKD patients. The HDL level showed an inverse correlation with right CCA and ICA. Conclusion Patients with CKD have an increased waist-to-hip ratio, dyslipidemia, and increased carotid IMT, which are factors that lead to the early development of atherosclerosis. Special care should be directed to CKD patients, especially those in stages 2-4, to control their lipid profile and postpone the development of atherosclerosis as much as possible.

AYURVEDIC MANAGEMENT OF DYSLIPIDEMIA – A CONCEPTUAL ANALYSIS

Dyslipidemia is among the most common lifestyle disorders characterised by a derangement in lipoprotein metabolism, which can lead to excessive production or deficiency of lipoproteins or both. Increased levels of atherogenic lipoproteins contribute to the occurrence of atherosclerosis, which in turn leads to coronary artery disease (CAD), cerebrovascular accidents (CVA), peripheral vascular diseases (PVD), etc. Dyslipidemia typically does not present with symptoms and often goes unnoticed until complications arise, such as myocardial infarction, triggered by the development of early atherosclerosis. In Ayurveda, lipid disorders are correlated with Medapradoshaja vikara.(diseases due to vitiated fat) Conditions like Medoroga,(lipid disorders) Sthoulya (obesity), Shonita Abhishyanda (increased sliminess and heaviness of blood) etc. are caused due to Dushti (vitiation) of Medodhatu.(fat tissue) Therefore; these conditions share similarities in their management approaches also. Ayurvedic strategies for addressing Medoroga involve treatments such as Rukshana (drying), Udvartana (dry powder massage), Ruksha-ushna basti (dry and hot medicated enema), Virechana (purgation), and oral medications like Guggulu (Commiphora mukul), Shilajithu (Asphaltum), Guduchi (Tinospora cordifolia) etc. Contemporary science advises different classes of medications for the management of dyslipidemia. Most of the medications are reported to have adverse effects. Hence it is essential to find some safe and effective lines of management. This can be achieved through Ayurvedic therapeutic procedures as well as oral medications.

Diagnosis of Familial Hypercholesterolemia in Children and Young Adults.

The early detection and treatment of familial hypercholesterolemia (FH) in childhood and adolescence are critical for increasing life expectancy. The purpose of our study was to investigate blood lipid parameters, features of physical signs of cholesterol accumulation, and a personal and family history of premature cardiovascular diseases in children and young adults when FH is diagnosed. The analysis included patients under 18 years of age (n = 17) and young adults (18-44 years of age; n = 43) who received a diagnosis of FH according to clinical criteria. Targeted high-throughput sequencing was performed using a custom panel of 43 genes. A family history of cardiovascular diseases was more often noted in the group under 18 years of age than in young adults (p < 0.001). Among young adults, there was a high prevalence of typical signs of the disease such as tendon xanthomas and the early development of arterial atherosclerosis (p < 0.001). By molecular genetic testing, "pathogenic" and "probably pathogenic" variants were identified in the genes of 73.3% of patients under 18 years of age and 51.4% of patients 18-44 years of age. Thus, blood lipid screening tests combined with an accurate assessment of the family history is a highly relevant and inexpensive option for diagnosing FH in childhood. Molecular genetic testing allows us to make an accurate diagnosis and to improve adherence to treatment.

Identification of c.683_684insCTGCAAGGACAAATCTGACGA pathogenic variant of the low-density lipoprotein receptor gene in a patient with familial hypercholesterolemia: a case report

Familial hypercholesterolemia (FH) is one of the most common monogenic diseases that leads to the early development of atherosclerosis and is characterized by a poor prognosis. However, only about 1% of FH cases are diagnosed in Russia. The aim of this study was to determine the genetic defect in the FH family and conduct DNA diagnostics in the proband relatives. The study was performed on blood samples obtained with the informed consent of the patients. Polymerase chain reaction and polyacrylamide gel electrophoresis were used. We report c.683_684insCTGCAAGGA CAAATCTGACGA pathogenic variant of the low-density lipoprotein receptor (LDLR) gene for the first time in Russia and demonstrate its cosegregation in a family with high blood cholesterol. The c.683_684in sCTGCAAGGACAAATCTGACGA insertion is considered as a probable cause of FH.

Gene deletion of Interleukin-1α reduces ER stress-induced CHOP expression in macrophages and attenuates the progression of atherosclerosis in apoE-deficient mice

The pathophysiology of atherosclerosis initiation and progression involves many inflammatory cytokines, one of them is interleukin (IL)-1α that has been shown to be secreted by activated macrophages. We have previously shown that IL-1α from bone marrow-derived cells is critical for early atherosclerosis development in mice. It is known that endoplasmic reticulum (ER) stress in macrophages is involved in progression to more advanced atherosclerosis, but it is still unknown whether this effect is mediated through cytokine activation or secretion. We previously demonstrated that IL-1α is required in ER stress-induced activation of inflammatory cytokines in hepatocytes and in the associated induction of steatohepatitis. In the current study, we aimed to examine the potential role of IL-1α in ER stress-induced activation of macrophages, which is relevant to progression of atherosclerosis. First, we demonstrated that IL-1α is required for atherosclerosis development and progression in the apoE knockout (KO) mouse model of atherosclerosis. Next, we showed that ER stress in mouse macrophages results in the protein production and secretion of IL-1α in a dose-dependent manner, and that IL-1α is required in ER stress-induced production of the C/EBP homologous protein (CHOP), a critical step in ER stress-mediated apoptosis. We further demonstrated that IL-1α-dependent CHOP production in macrophages is specifically mediated through the PERK-ATF4 signaling pathway. Altogether, these findings highlight IL-1α as a potential target for prevention and treatment of atherosclerotic cardiovascular disease.

Small extracellular vesicles from pregnant women with maternal supraphysiological hypercholesterolemia impair endothelial cell function in vitro

Maternal physiological hypercholesterolemia MPH, maternal total cholesterol (TC) levels at term of pregnancy ≤280 mg/dL) occurs to assure fetal development. Maternal supraphysiological hypercholesterolemia (MSPH, TC levels >280 mg/dL) is a pathological condition associated with maternal, placental, and fetal endothelial dysfunction and early neonatal atherosclerosis development. Small extracellular vesicles (sEVs) are delivered to the extracellular space by different cells, where they modulate cell functions by transporting active signaling molecules, including proteins and miRNA. AimTo determine whether sEVs from MSPH women could alter the function of endothelial cells (angiogenesis, endothelial activation and nitric oxide synthesis capacity). MethodsThis study included 24 Chilean women (12 MPH and 12 MSPH). sEVs were isolated from maternal plasma and characterized by sEV markers (CD9, Alix and HSP70), nanoparticle tracking analysis, transmission electron microscopy, and protein and cholesterol content. The endothelial cell line HMEC-1 was used to determine the uptake of labeled sEVs and the effects of sEVs on cell viability, endothelial tube formation, endothelial cell activation, and endothelial nitric oxide expression and function. ResultsIn MSPH women, the plasma concentration of sEVs was increased compared to that in MPH women. MSPH-sEVs were highly taken up by HMEC-1 cells and reduced angiogenic capacity and the expression and activity of eNOS without changing cell viability or endothelial activation compared to MPH-sEVs. ConclusionsEVs from MSPH women impair angiogenesis and nitric oxide synthesis in endothelial cells, which could contribute to MSPH-associated endothelial dysfunction.

Disturbance of intestinal permeability and its role in the development of cardiovascular complications in persons with inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are one of the most complex and significant problems of modern gastroenterology. The steady increase in morbidity, complex pathogenetic mechanisms of development, the presence of severe extra-intestinal manifestations and complications make this problem socially significant. The article presents modern views on some aspects of the pathogenesis of IBD. Currently, the key links in the development and progression of IBD, as well as the development of associated cardiovascular diseases are the state of the intestinal microbiota and the level of endotoxemia. The role of trimethylamine N-oxide as a factor in the early development of atherosclerosis in patients with IBD was determined.

Obesity as a comorbidity in children and adolescents with autoimmune rheumatic diseases.

Childhood obesity is the public health issue with alarming rates recorded throughout developed world and an important modifiable health risk for developing various chronic diseases, with childhood-onset autoimmune rheumatic diseases among them also. The aim of this article was to summarize epidemiological, pathophysiological and clinical implication of obesity on juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), juvenile dermatomyositis (JDM), IgA vasculitis (IgAV) and Kawasaki disease (KD). We reviewed PubMed database and selected 74 relevant articles. Epidemiological data of obesity among children with autoimmune rheumatic diseases indicate an increased prevalence of it. Pathophysiological link between obesity, humoral adipokines and cytokines released from fat tissue and childhood-onset autoimmune rheumatic diseases is complex and still not entirely clear. From the clinical point of view, obesity was not associated with disease activity in JIA and cSLE, but proved to contribute on functional impairment in both diseases and affect poor treatment response in JIA patients. Early atherosclerosis and cardiovascular disease (CVD) development in obese children and adolescents with JIA, cSLE and JDM are certainly important obesity-related complications. Understanding how obesity affects children and adolescents with autoimmune rheumatic diseases may encourage clinicians to consider taking better preventive strategies in this population to improve their long-term outcome.

Effect of PCSK9 inhibitors on cardio-ankle vascular index in familial hypercholesterolemia subjects

Background and Aims : Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of LDL-C that promotes a development of early atherosclerosis. Our aim was to evaluate the effect of PCSK9-i on atherosclerosis damage analyzed by cardio-ankle vascular index (CAVI) in a cohort of FH subjects.

Beta-Sitosterol Modulates the Migration of Vascular Smooth Muscle Cells via the PPARG/AMPK/mTOR Pathway

Introduction: The increased migration of vascular smooth muscle cells (VSMCs) is an essential pathological factor in the early development of atherosclerosis. Beta-sitosterol (BS), a natural phytosterol abundant in plant seeds, exhibits various bioactivities, including cardioprotective effects. However, its effects on VSMC migration and underlying mechanisms remain to be explored. Method and Result: BS inhibited the proliferation and migration of angiotensin II-induced A7r5 cells and reduced intracellular oxidative stress. Targets related to VSMC migration and the targets of BS were screened, cross-referenced, and analyzed by network pharmacology combined with molecular docking technology. The identified targets were verified at the protein and gene levels using Western blotting and quantitative PCR, respectively. BS was observed to activate peroxisome proliferator-activated receptor-γ (PPARG) and adenosine 5′-monophosphate-activated protein kinase (AMPK) and negatively regulate mammalian target of rapamycin (mTOR) expression. Furthermore, a PPARG inhibitor reversed the BS-induced activation of AMPK and mTOR. Conclusion: This study indicated that regulation of the PPARG/AMPK/mTOR signaling pathway could potentially contribute to the inhibitory effects of BS on angiotensin II-induced VSMC migration.

Особливості перебігу артеріальної гіпертензії, поєднаної з дисплазією сполучної тканини, у практиці сімейного лікаря

Актуальність. Поєднання артеріальної гіпертензії (АГ) та дисплазії сполучної тканини (ДСТ) є одним із недостатньо вивчених питань. ДСТ супроводжується порушеннями структури та функції судин, сприяє розвитку раннього атеросклерозу та серцево-судинних ускладнень. У хворих на АГ, поєднану з ДСТ, часто зустрічаються порушення ритму та провідності серця, значно поширені зміни з боку органів зору, внутрішніх органів та кістково-суглобової системи. Мета. Покращити діагностику та лікування АГ, поєднаної з ДСТ, на основі вивчення клінічного перебігу, вираженості зовнішніх і внутрішніх симптомів ДСТ, ліпідного спектра крові, гострофазових показників, сечової кислоти та інструментальних методів обстеження. Матеріали та методи. Проведено клінічне дослідження, в яке включено 75 хворих на АГ ІІ стадії 1–3-го ступеня з проявами ДСТ, середній вік яких становив 63,5 ± 4,2 року, які перебували на стаціонарному лікуванні в кардіологічному відділенні Комунальної міської клінічної лікарні швидкої медичної допомоги м. Львова. Методи дослідження включали клінічні (огляд, пальпація, перкусія, аускультація), лабораторні (ліпідний спектр крові, С-реактивний протеїн, серомукоїди та сечова кислота), інструментальні (електрокардіографія, ехокардіографія, добове моніторування артеріального тиску, езофагогастродуоденоскопія, ультразвукове дослідження (УЗД) внутрішніх органів і судин нижніх кінцівок, УЗ-дуплексне обстеження сонних і хребтових артерій, рентгенологічне дослідження кістково-суглобової системи), консультації офтальмолога, невропатолога, травматолога, стоматолога. Діагностика недиференційованої ДСТ визначалася за методикою Т.М. Кадуріної та співавт. (2009). Розрахунок діагностичного коефіцієнта для кожної ознаки дисплазії проводили за методикою, розробленою В.М. Яковлевим та співавт. (2008). Пацієнти були розподілені на 3 групи:1-ша група — 12 пацієнтів з АГ II стадії 1-го ступеня, 2-га група — 26 пацієнтів з АГ II стадії 2-го ступеня, 3-тя група — 30 пацієнтів з АГ II стадії 3-го ступеня. Контрольна група — 7 пацієнтів з АГ ІІ стадії 1–3-го ступеня без проявів ДСТ. Результати. При порівняльному аналізі хворих з АГ у 90,67 % спостерігався ряд зовнішніх і внутрішніх симптомів дисплазії сполучної тканини, у 9,33 % були відсутні прояви ДСТ. У 3-й групі хворих спостерігали більше зовнішніх і внутрішніх фенотипових ознак ДСТ та їх вираженість порівняно з 1-ю та 2-ю групами, що прогнозує тяжкість клінічного перебігу захворювання. Висновки. У хворих на АГ спостерігається значне поширення ДСТ: чим більше ознак ДСТ, тим тяжчий клінічний перебіг гіпертонії. У хворих з АГ, поєднаною з ДСТ, поширені зміни з боку серцево-судинної системи, органів зору, внутрішніх органів та кістково-суглобової системи порівняно з групою хворих без ДСТ. При порівнянні групи хворих з АГ і наявністю ДСТ відмічаються вищі показники активності запального процесу та ліпідного спектра крові, ніж у хворих без ДСТ. Своєчасне виявлення АГ, поєднаної з ДСТ, систематичний диспансерний нагляд за хворими, проведення комплексу заходів, спрямованих на покращення структури та функції сполучної тканини, корекція імунодефіциту дозволяють покращити результати перебігу даної патології.

Association of Serum Adiponectin Level with Dyslipidaemia in North Indian Male Population: A Case-control Study

Introduction: Adiponectin is the most abundant adipocytokines secreted from adipose tissues and circulates in considerably high concentration in human plasma. Circulating adiponectin levels are decreased in obese subjects and this decrease has been thought to play a crucial role in the early development of atherosclerosis and cardiovascular diseases. Changes in adiponectin concentration has been reported in dyslipidemic subjects, but the evidence is controversial and no study conducted in north Indian population. Moreover, low molecular adiponectin seems to be linked with a worse lipid profile leading to dyslipidaemic through an association with triglyceride but the exact role of adiponectin in modulating lipid fraction is not well established. Aim: To correlate the level of serum adiponectin with lipid fractions in dyslipidemic male subjects and also to compare them with apparently healthy individuals. Materials and Methods: This case control study was conducted from April 2015 to November 2016 in the Biochemistry department of Rajshree Medical Research institute, Bareilly, Uttar Pradesh, India. A total of 70 non diabetic dyslipidemic male subjects between the age group 35 years to 55 years were selected and all the biochemical parameters (adiponectin, fasting plasma glucose, lipid profile) were evaluated and compared with 70 apparently healthy controls. Statistical analysis was performed by licensed version of Statistical Package for Social Sciences (SPSS) 16.0 software. All the data were expressed in “mean±SD”. Student ‘t’ test was also applied to see statistical significance in adiponectin levels between dyslipidemic subjects and healthy controls. Results: The study shows mean±SD of age in dyslipidemic group was 43.61±4.85 years and for control group was 43.53±5.53 years. The mean±SD of BMI in dyslipidemic group 25.72±2.43 was significantly higher than control group 23.42±1.56 with p-value &lt;0.0001. The serum adiponectin concentration was significantly reduced in dyslipidemic subjects 5.11±2.04 μg/mL as compared to healthy control 6.79±1.37 μg/mL with p-value &lt;0.0001. Serum total cholesterol, triglyceride and Low Density Lipoprotein (LDL)- cholesterol were found to be negatively correlated with serum adiponectin (r= -0.89, -0.76 and -0.74) and positively correlated with High Density Lipoprotein (HDL)-cholesterol (r= 0.70). Conclusion: The present study revealed that hypoadiponectinemia is associated with dyslipidaemic in men. The main observation of our present study, however, is that in dyslipidemic subjects, lower levels of adiponectin were associated with high total cholesterol, triglyceride, LDL-cholesterol and reduced HDL cholesterol, though more extensive, multicentric, prospective research with increase sample size could obtain wider insights.

Ischemic Heart Disease and Heterozygous Familial Hypercholesterolemia: the Problem of Diagnosis and Treatment (Clinical Case)

Familial hypercholesterolemia (FH) is a genetic disorder, characterized by high blood cholesterol levels, particularly – very high low-density lipoprotein (LDL) levels, which leads to the development of cardiovascular disease at a young age. Heterozygous FH is diagnosed in the general population in most countries in one of 500 people. Certain phenotypic manifestations of this disease have been identified, namely: tendon xanthomas, lipid arch of the cornea and xanthelasma. Patients with FH are prone to early development of atherosclerosis and clinically manifest forms of cardiovascular diseases, in particular ischemic heart disease. A direct correlation has been established between morbidity, mortality from coronary heart disease and blood cholesterol level. It has also been proven that hypercholesterolemia is the main risk factor for the development of atherosclerosis and its complications. Early diagnosis and modern lipid-lowering therapy play an important role for patients with signs of hereditary lipid metabolism disorders. Patients with heterozygous FH are usually treated by statins, which act by inhibiting an enzyme in the liver. Statins are effective in lowering total cholesterol and LDL levels. Sometimes other drugs are additionally prescribed. The diagnosis of this pathology requires a genetic consultation. All patients with FH require lifelong pharmacological therapy. The use of statins leads to a decrease in coronary mortality by 25–40%, and decrease in the risk of ischemic events – by 26–30%. An observational study of a large British registry noted that mortality in patients with FH began to decline slightly from the early 90s of the XX century, when statins were started to use in treatment. The article presents a clinical case of ischemic heart disease in heterozygous FH patent, considers diagnostic criteria and modern approaches to the management of patients with hereditary disorders of lipid metabolism.

The features of Sphingolipids’ profile in young patients with atherothrombotic stroke

Background and Aims: Sphingolipids may contribute to the development of early atherosclerosis. The aim of the study is to determine the features of sphingolipids profile in young patients with stroke.

The benzoate plant metabolite ethyl gallate prevents cellular- and vascular-lipid accumulation in experimental models of atherosclerosis

Ethyl gallate (EG) is a well-known constituent of medicinal plants, but its effects on atherosclerosis development are not clear. In the present study, the anti-atherosclerosis effects of EG and the underlying mechanisms were explored using macrophage cultures, zebrafish and apolipoprotein (apo) E deficient mice. Treatment of macrophages with EG (20 μM) enhanced cellular cholesterol efflux to HDL, and reduced net lipid accumulation in response to oxidized LDL. Secretion of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) from activated macrophages was also blunted by EG. Fluorescence imaging techniques revealed EG feeding of zebrafish reduced vascular lipid accumulation and inflammatory responses in vivo. Similar results were obtained in apoE-/- mice 6.5 months of age, where plaque lesions and monocyte infiltration into the artery wall were reduced by 70% and 42%, respectively, after just 6 weeks of injections with EG (20 mg/kg). HDL-cholesterol increased 2-fold, serum cholesterol efflux capacity increased by ∼30%, and the levels of MCP-1 and IL-6 were reduced with EG treatment of mice. These results suggest EG impedes early atherosclerosis development by reducing the lipid and macrophage-content of plaque. Underlying mechanisms appeared to involve HDL cholesterol efflux mechanisms and suppression of pro-inflammatory cytokine secretion.

SATURATED FATTY ACIDS IN ERYTHROCYTE MEMBRANES IN ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS

Objective: Type 1 diabetes mellitus (T1DM) is associated with early development of atherosclerosis. The aim of this study was to assess the association between saturated fatty acids (SFAs) contained in erythrocyte membranes and some indices of vascular damage in a sample of adolescents with T1DM. Design and method: Participants in regular follow-up at the Paediatric Diabetology Unit of Verona were sent for evaluation at the Vascular Laboratory of the General Medicine &amp; Hypertension Unit Central blood pressure (BP), Pulse Wave Velocity (PWV) and Pulse Wave Analysis (PWA) were measured by the SphygmoCor Xcel, carotid Intima Media Thickness (cIMT) and carotid distensibility (DC) by ultrasound and elaborated with a dedicated hardware. Blood samples were evaluated for erythrocyte membrane SFA, expressed as a percentage of total Fatty Acids (FAs). Results: Hundred and forty-seven adolescents (78 males and 69 females, mean age 17,25 ± 1,93 years) were studied. Fifteen patients were classified as hypertensive (10,2%) according to current European Guidelines. Thirteen patients had central systolic BP (cSBP) (8,8%), 60 cIMT (40,8%), 49 (33,3%) DC and 1 PWV (0,7%) above the 95th percentile for sex and age/height. We observed a correlation between total SFAs and cSB and z-cSBP (r = 0,260 and 0,269 respectively, p &lt; 0,05), not confirmed when each SFA was analysed separately. Furthermore, a positive correlation between total SFAs and either PWV or z-PWV was detectable (r = 0,241 and 0,251 respectively, p &lt; 0,05). The latter association remained significant even after adjustment for age, sex, Body Mass Index (BMI), duration of diabetes, HbA1c, total cholesterol, triglycerides-HDL ratio. Total SFAs were also associated with BMI (r = 0,191, p &lt; 0,05). Conclusions: Erythrocyte membrane FAs are associated with vascular (cSBP and PWV) and anthropometric parameters in patients with T1DM. The amount of SFAs in membranes does not depend only on diet, as they are also neo-synthetized from glucidic precursors. Thus, it can be speculated that a bad glycemic control could translate into a higher substrate amount to produce the different SFAs. Further studies are needed to better understand the mechanisms and the regulations of these pathways

Artemisinin protects endothelial function and vasodilation from oxidative damage via activation of PI3K/Akt/eNOS pathway.

Previous studies showed that artemisinin (ART) may be useful in the protection against the early development of atherosclerosis, but the effects of ART on vasodilation and eNOS remained unclear. In the current study, we investigated the protective effect of ART on endothelial cell injury induced by oxidative stress and its underlying mechanism via MTT assay, Flow Cytometry Assay, Vasodilation study, Western blotting and vivo assay. We found that pretreatment of human umbilical vein endothelial cells (HUVECs) with ART significantly suppressed H2O2-induced cell death by decreasing the extent of oxidation and MDA activity, activating SOD, increasing NO production and inhibiting caspase 3/7 activity. Meanwhile, we also found that ART was able to activate PI3K/Akt/eNOS pathway. PI3K inhibitor LY294002 or Akt kinase specific inhibitor Akt inhibitor VIII blocked the protective effect of ART. To explore the effect of ART in the damage of vasodilation induced by H2O2 in mice, we treated the aortic ring from C57BL/6 mice with H2O2 with or without ART, the results demonstrated that ART ameliorated endothelium-dependent vasodilation damage induced by H2O2. Taken together, these data suggest that ART is able to protect endothelial function and vasodilation from oxidative damage, at least in part through activation of PI3K/Akt/eNOS pathway. Our findings indicate that artemisinin maybe as a potential therapeutic agent for patients with atherosclerosis.

Insulin Resistance and Ischemic Etiology Heart Failure: Is There an Interrelationship in Clinical Practice?

Background. IR promotes the development of early atherosclerosis and may increase the risk of cardiovascular complications, which is of great importance in patients with CHF. Thus, the assessment of the relationship between IR and clinical indicators of CHF is relevant in the clinical aspect and needs more detailed research. Objective: To evaluate the relationship between IR and clinical parameters in hospitalized ischemic etiology CHF patients without concomitant CMD. Methods. The study included 174 hospitalized patients with a stable course of CHF FC III (NYHA) and CAD from 18 to 65 years old, without previously identified CMD. Anthropological, clinical, laboratory examination was carried out. The neurohormonal profile included insulin (IR by HOMA- IR), aldosterone, and Nt-proBNP levels. To study the relationship of IR with clinical parameters in CHF and CAD patients, a correlation analysis was performed. Results. A statistically significant relationship between IR and the following parameters was revealed: BMI (r = 0.186, p = 0.045), total FINDRISC score (r = 0.386, p = 0.000), SBP (r = 0.247, p = 0.007), DBP (r = 0.173, p = 0.063), HbA1c (r = 0.388, p = 0.000), insulin concentration (r = 0.833, p = 0.000). To identify independent predictors influencing IR, we carried out multivariate linear regression analysis with stepwise inclusion of indicators in the model, in which HOMA-IR was used as a dependent variable, and BMI, total FINDRISK scores, SBP, DBP, HbA1c levels were included as independent variables. It turned out that the independent factors associated with IR are: HbA1c (β = 0.144; p = 0.000) and the FINDRISK scale points (β = 0.064; p = 0.05). Conclusions. In patients with CHF and CAD, IR is interrelated with such indicators as BMI, FINDRISC total points, SBP, DBP, HbA1c. Independent predictors influencing IR are HbA1c and the FINDRISK total points.

Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos)

Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5–10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.

Tc17 CD8+ T cells accumulate in murine atherosclerotic lesions, but do not contribute to early atherosclerosis development.

AimsCD8+ T cells can differentiate into subpopulations that are characterized by a specific cytokine profile, such as the Tc17 population that produces interleukin-17. The role of this CD8+ T-cell subset in atherosclerosis remains elusive. In this study, we therefore investigated the contribution of Tc17 cells to the development of atherosclerosis.Methods and resultsFlow cytometry analysis of atherosclerotic lesions from apolipoprotein E-deficient mice revealed a pronounced increase in RORγt+CD8+ T cells compared to the spleen, indicating a lesion-specific increase in Tc17 cells. To study whether and how the Tc17 subset affects atherosclerosis, we performed an adoptive transfer of Tc17 cells or undifferentiated Tc0 cells into CD8−/− low-density lipoprotein receptor-deficient mice fed a Western-type diet. Using flow cytometry, we showed that Tc17 cells retained a high level of interleukin-17A production in vivo. Moreover, Tc17 cells produced lower levels of interferon-γ than their Tc0 counterparts. Analysis of the aortic root revealed that the transfer of Tc17 cells did not increase atherosclerotic lesion size, in contrast to Tc0-treated mice.ConclusionThese findings demonstrate a lesion-localized increase in Tc17 cells in an atherosclerotic mouse model. Tc17 cells appeared to be non-atherogenic, in contrast to their Tc0 counterpart.