Development Of Arteriosclerosis Research Articles

Association between Inflammation, Glycocalyx Biomarkers, and Endothelial Function in Children with Hypercholesterolemia

Introduction: Hypercholesterolemia is a risk factor for premature arteriosclerosis. Inflammation and oxidative stress are thought to contribute to endothelial dysfunction preceding vasculopathy. We investigated the association between inflammation, glycocalyx biomarkers, endothelial function, and vascular parameters in children with hypercholesterolemia. Methods: In 22 patients (LDL-cholesterol >130 mg/dL; median age [IQR]: 13 [2.3] years) and 22 controls (13 [2.5] years), tumor necrosis factor-alpha (TNF-α), oxidized cholesterol (oxLDL), and glycocalyx biomarkers (Syndecan-1, Hyaluronan) were measured using immunoassays. Endothelial function was assessed by peripheral arterial tonometry, sublingual glycocalyx and microcirculation by videomicroscopy and carotid intima-media thickness by ultrasound. Results: OxLDL was significantly higher in patients (78.9 [38.2] vs. 50.3 [16.6] U/L, p = 0.002), whereas all other experimental parameters were comparable between groups. Multivariate analysis revealed a significant association of Syndecan-1 with TNF-α (β = 0.75, p p = 0.030). The interaction term combining TNF-α and hypercholesterolemia showed a significant effect (p = 0.034). Sex was an independent predictor of endothelial function. Conclusion: The combined effect of hypercholesterolemia and inflammation on glycocalyx perturbation and the impact of sex in the premature development of arteriosclerosis deserve further evaluation. Therapeutic approaches tackling low-grade systemic inflammation may offer potential to prevent or delay progression of cardiovascular disease and cardiovascular complications.

Progression of arterial calcifications: what, where, and in whom?

ObjectivesThere is a lack of information on the development of arteriosclerosis over time. This study aims to assess long-term sex-specific changes in arterial calcifications in five arteries, and the influence of cardiovascular risk factors hereon.MethodsFrom a population-based cohort, 807 participants (mean baseline age, 65.8; SD, 4.2) underwent a non-contrast computed tomography (CT) examination between 2003 and 2006, and after a median follow-up of 14 years. We assessed incidences and changes in volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC), and vertebrobasilar artery calcification (VBAC). We investigated the simultaneous presence of severe progression (upper quartile of percentual change volumes). Associations of cardiovascular risk factors with changes in calcification volumes were assessed using multivariate linear regression models.ResultsThe difference in AAC was most substantial; the median volume (mm3) increased from of 129 to 916 in men and from 93 to 839 in women. For VBAC, no change in volumes was observed though more than a quarter of participants without baseline VBAC developed VBAC during follow-up. Severe progression was most often observed in only one artery at the same time. Hypertension was most consistently associated with increase in calcifications. Associations of diabetes, hypercholesterolemia, and smoking with changes in calcifications varied across arteries and sex.ConclusionsWe found a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors were associated with increase of calcifications with sex-specific differential effects across arteries.Clinical relevance statementThere is a considerable incidence and increase in volumes of calcifications in different arteries, over a 14-year time interval. Cardiovascular risk factors are associated with increase of calcifications with sex-specific differential effects across arteries; thus, assessing changes in only one artery may thus not provide a good reflection of the systemic development of arteriosclerosis.Key Points• Assessing change in arterial calcification in only one artery does not reflect the systemic development of arterial calcification.• Cardiovascular risk factors are associated with progression of arterial calcifications.• Progression of arterial calcification is sex and artery-specific.Graphical

Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging.

Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

INCREASED IONIZED CALCIUM-MAGNESIUM RATIO IN ELDERLY HYPERTENSIVES

Objective: Alterations in the metabolism of calcium and the biofactor magnesium can be involved in the pathogenesis of essential hypertension. Serum magnesium concentrations only insufficiently reflect disorders in magnesium handling in humans, as only about 1% of total body magnesium stores are in blood. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium and magnesium (TRPM 6 and 7) channels and a sodium magnesium antiport. An increased calcium-magnesium ratio is known to be involved in the development of atherosclerosis. Early onset of this disorders are known in hypertension. Design and method: We present a study in 18 hypertensive elderly concerning ionized magnesium concentrations and ionized calcium-magnesium ratio in blood measured by a Prime Plus apparatus by NOVA Medical, Andover, USA. Results: In 18 elderly hypertensives (9 male/9 female with normal renal function) ionized magnesium was measured 0.55 +/- 0.04 mmol/l (normal range: 0.54 - 0.80 mmol/l). The ionized calcium-magnesium ratio was 2.33 +/- 0.18 (normal range below 2.40)(p< 0.05). Data are means +/- SD. ANOVA was used for statistical evaluation. About 40% of elderly hypertensives showed an significantly increased ratio of ionized calcium and magnesium, which is well known to be a marker for the development of arteriosclerosis. Conclusions: As described earlier, a deficiency in the biofactor magnesium can be involved in the pathogenesis of essential hypertension. Ionized magnesium data, as presented here, are rare, but ionized magnesium is the active magnesium in the body regulating about 600 enzymatic reactions. The significantly increased ratio of ionized calcium and magnesium is important in the development of arteriosclerosis often resulting in stroke or heart insufficiency in hypertension.

The gut microbiome: a core regulator of metabolism.

The human body is inhabited by numerous bacteria, fungi, and viruses, and each part has a unique microbial community structure. The gastrointestinal tract harbors approximately 100 trillion strains comprising more than 1000 bacterial species that maintain symbiotic relationships with the host. The gut microbiota consists mainly of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Of these, Firmicutes and Bacteroidetes constitute 70-90% of the total abundance. Gut microbiota utilize nutrients ingested by the host, interact with other bacterial species, and help maintain healthy homeostasis in the host. In recent years, it has become increasingly clear that a breakdown of the microbial structure and its functions, known as dysbiosis, is associated with the development of allergies, autoimmune diseases, cancers, and arteriosclerosis, among others. Metabolic diseases, such as obesity and diabetes, also have a causal relationship with dysbiosis. The present review provides a brief overview of the general roles of the gut microbiota and their relationship with metabolic disorders.

Sex-specific association of serum uric acid trajectories with risk of incident retinal arteriosclerosis in Chinese population: A population-based longitudinal study.

The impact of serum uric acid (SUA) trajectories on the development of retinal arteriosclerosis is uncertain. The purpose of this study was to identify adult SUA trajectories by sex and determine their association with risk of retinal arteriosclerosis. In this longitudinal study, 4,324 participants who were aged between 18 and 60 years without retinal arteriosclerosis at or before baseline (from January 1, 2010, through December 31, 2010) were included. Group-based trajectory modeling was used to identify SUA trajectories during the exposure period (from January 1, 2006, through December 31, 2010). Cox proportional-hazards models were applied to evaluate the associations between SUA trajectories and the risk of incident retinal arteriosclerosis during the outcome period (from January 1, 2011, through December 31, 2019). 4 distinct SUA trajectories were identified in both women and men: low, moderate, moderate-high, and high. During a median follow-up of 9.54 years (IQR 9.53-9.56), 97 women and 295 men had developed retinal arteriosclerosis. In the fully adjusted model, a significant association between the moderate-high SUA trajectory group and incidence of retinal arteriosclerosis was observed only in men (HR: 1.76, 95% CI: 1.17-2.65) compared with the low trajectory group, but not in women (HR: 0.77, 95% CI: 0.39-1.52). Also, the high SUA trajectory group had the highest risk with an adjusted HR of 1.81 (95% CI, 1.04-3.17) in men. However, they did not exhibit a substantially increased risk in women. Higher SUA trajectory groups were significantly associated with an increased risk of incident retinal arteriosclerosis in men but not in women.

Temporal longitudinal associations of carotid-femoral pulse wave velocity and carotid intima-media thickness with resting heart rate and inflammation in youth.

We examined the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT) with the risk of elevated resting heart rate (RHR) and high-sensitivity C-reactive protein (hsCRP). We studied 3,862 adolescents, mean age 17.7 (SD 0.3 yr), followed-up for 7 yr until age 24.5 (0.7) yr, from the Avon Longitudinal Study of Parents and Children, UK. RHR, fasting plasma hsCRP, cfPWV, and cIMT were repeatedly assessed and analyzed using logistic regression, linear mixed-effect, and structural equation models adjusting for important covariates. Among 3,862 adolescents [2,143 (55.5%) female], 10% and 44% were at moderate-to-high risk of elevated RHR and hsCRP at 24.5 yr, respectively. Higher cfPWV at 17.7 yr was associated with elevated RHR risk at follow-up [odds-ratio (OR) 1.58 (CI 1.20-2.08); P = 0.001], whereas cIMT at 17.7 yr was associated with elevated hsCRP risk [OR 2.30 (1.18-4.46); P = 0.014] at follow-up, only among females. In mixed model, 7-yr progression in cfPWV was directly associated with 7-yr increase in RHR [effect-estimate 6 beats/min (1-11); P = 0.017] and hsCRP. cIMT progression was associated with 7-yr increase in RHR and hsCRP. In cross-lagged model, higher cfPWV at 17.7 yr was associated with higher RHR (β = 0.06, standard error = 3.85, P < 0.0001) at 24.5 yr but RHR at 17.7 yr was unassociated with cfPWV at 24.5 yr. Baseline cIMT or RHR was unassociated with either outcome at follow-up. Higher hsCRP at 17.7 yr was associated with higher cfPWV and cIMT at 24.5 yr. In conclusion, adolescent arterial stiffness but not cIMT appears to precede higher RHR in young adulthood, whereas elevated hsCRP in adolescence preceded higher cfPWV and cIMT.NEW & NOTEWORTHY Higher arterial stiffness but not carotid-intima media thickness in adolescence preceded higher resting heart rate in young adulthood, however, elevated high sensitivity C-reactive protein in adolescence preceded higher arterial stiffness and carotid intima-thickness in young adulthood in the temporal causal path. Low-grade inflammation during adolescence may be causally associated with the development of subclinical arteriosclerosis and atherosclerosis in young adulthood.

Association of Urinary Lead and Cadmium Levels, and Serum Lipids with Subclinical Arteriosclerosis: Evidence from Taiwan.

Exposure to lead and cadmium has been linked to changes in lipid metabolism and the development of arteriosclerosis, but the role of lipoprotein profiles in this relationship is not well understood, including the potential role of novel lipid biomarkers. In this study, we enrolled 736 young Taiwanese subjects aged 12 to 30 years to assess the correlation between urine levels of lead and cadmium, lipoprotein profiles, and carotid intima-media thickness (CIMT). Higher levels of lead and cadmium were significantly associated with higher levels of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), and CIMT. Participants with higher levels of lead and cadmium had the highest mean values of CIMT, LDL-C, sdLDL-C, and LDL-TG. In a structural equation model, lead had a direct and indirect association with CIMT through LDL-C and sdLDL-C, whereas cadmium had a direct association with CIMT and an indirect association through LDL-C. Our results suggest higher levels of lead and cadmium are associated with abnormal lipid profiles and increased CIMT. These heavy metals could have additive effects on lipids and CIMT, and the relationship between them may be mediated by lipoprotein levels. Further research is needed to determine the causal relationship.

Mechanisms of sympathoexcitation via P2Y6 receptors.

Many drugs used in cardiovascular therapy, such as angiotensin receptor antagonists and beta-blockers, may exert at least some of their actions through effects on the sympathetic nervous system, and this also holds true for e.g., P2Y12 antagonists. A new target at the horizon of cardiovascular drugs is the P2Y6 receptor which contributes to the development of arteriosclerosis and hypertension. To learn whether P2Y6 receptors in the sympathetic nervous system might contribute to actions of respective receptor ligands, responses of sympathetic neurons to P2Y6 receptor activation were analyzed in primary cell culture. UDP in a concentration dependent manner caused membrane depolarization and enhanced numbers of action potentials fired in response to current injections. The excitatory action was antagonized by the P2Y6 receptor antagonist MRS2578, but not by the P2Y2 antagonist AR-C118925XX. UDP raised intracellular Ca2+ in the same range of concentrations as it enhanced excitability and elicited inward currents under conditions that favor Cl- conductances, and these were reduced by a blocker of Ca2+-activated Cl- channels, CaCCInh-A01. In addition, UDP inhibited currents through KV7 channels. The increase in numbers of action potentials caused by UDP was not altered by the KV7 channel blocker linopirdine, but was enhanced in low extracellular Cl- and was reduced by CaCCInh-A01 and by an inhibitor of phospholipase C. Moreover, UDP enhanced release of previously incorporated [3H] noradrenaline, and this was augmented in low extracellular Cl- and by linopirdine, but attenuated by CaCCInh-A01. Together, these results reveal sympathoexcitatory actions of P2Y6 receptor activation involving Ca2+-activated Cl- channels.

Serum osteocalcin concentration as an independent biomarker of osteoporosis in patients with chronic kidney disease.

Osteocalcin, an osteoblast-derived hormone, is associated with the development of osteoporosis and arteriosclerosis in the general population. However, its role on the pathogenesis of osteoporosis and vascular calcification in patients with chronic kidney disease (CKD) is unclear. Here, we investigated the connection between osteocalcin, bone mineral density (BMD), and abdominal aortic calcification (AAC) in CKD patients. In total, 95 patients with stage 2 to stage 5 CKD were enrolled. Serum osteocalcin levels were measured using an electrochemiluminescence immunoassay. BMD was determined by dual-energy X-ray absorptiometry, and AAC scores were generated from lateral lumbar radiograph findings. 95 patients were assigned into normal bone density (30.5%, n = 29), osteopenia (45.3%, n = 43), and osteoporosis (24.2%, n = 23) groups. The osteoporosis group was characterized by older age, higher female-to-male ratio, phosphorous levels, calcification scores, osteocalcin levels, and intact parathyroid hormone (PTH) levels, while with lower hemoglobin levels as compared to normal and osteopenia groups. Multivariate multinominal regression analysis showed age, female sex, intact PTH, and serum osteocalcin level were independent determinants of osteoporosis severity in CKD patients. Furthermore, serum osteocalcin level is positively correlated to intact PTH in multivariate linear regression model, indicating that osteocalcin might be a bone turnover marker in patients with CKD. Multivariate stepwise linear regression analysis revealed that age, diabetes mellitus, poorer renal function, rather than osteocalcin, have independent associations with AAC score. Elevated serum osteocalcin levels could be considered as a marker of osteoporosis rather than that of vascular calcification in patients with CKD.

Influence of local aortic calcification on periaortic adipose tissue radiomics texture features—a primary analysis on PCCT

Perivascular adipose tissue is known to be metabolically active. Volume and density of periaortic adipose tissue are associated with aortic calcification as well as aortic diameter indicating a possible influence of periaortic adipose tissue on the development of aortic calcification. Due to better spatial resolution and signal-to-noise ratio, new CT technologies such as photon-counting computed tomography may allow the detection of texture alterations of periaortic adipose tissue depending on the existence of local aortic calcification possibly outlining a biomarker for the development of arteriosclerosis. In this retrospective, single-center, IRB-approved study, periaortic adipose tissue was segmented semiautomatically and radiomics features were extracted using pyradiomics. Statistical analysis was performed in R statistics calculating mean and standard deviation with Pearson correlation coefficient for feature correlation. For feature selection Random Forest classification was performed. A two-tailed unpaired t test was applied to the final feature set. Results were visualized as boxplots and heatmaps. A total of 30 patients (66.6% female, median age 57 years) were enrolled in this study. Patients were divided into two subgroups depending on the presence of local aortic calcification. By Random Forest feature selection a set of seven higher-order features could be defined to discriminate periaortic adipose tissue texture between these two groups. The t test showed a statistic significant discrimination for all features (p < 0.05). Texture changes of periaortic adipose tissue associated with the existence of local aortic calcification may lay the foundation for finding a biomarker for development of arteriosclerosis.

Influence of risk factors for the development of cardiovascular diseases on the parameters of arterial stiffness in patients with arterial hypertension and atherosclerosis of different degrees of severity

BACKGROUND: Arterial hypertension is widespread in the population, leads to the development of arteriosclerosis and increase of arterial stiffness, and is the main non-lipid risk factor of atherosclerosis development. Multiple studies have shown that increase of arterial stiffness is an independent risk factor for the development of cardiovascular events. However, the influence of traditional cardiovascular risk factors on arterial stiffness in arterial hypertension and atherosclerotic process of different degrees of severity has not been sufficiently studied.&#x0D; AIM: To assess the influence of traditional risk factors on the parameters of arterial stiffness in patients with arterial hypertension (AH) and atherosclerotic process of varying degrees of severity.&#x0D; MATERIALS AND METHODS: 133 subjects with AH have been divided into 3 groups depending on the severity of the atherosclerotic process. The control group included 33 individuals without known cardiovascular diseases. All the participants have undergone a standard clinical and laboratory examination, 24hr blood pressure monitoring with assessment of arterial stiffness (AS) parameters. The influence of risk factors on AS parameters has been analyzed for all the participants and separately by groups.&#x0D; RESULTS: In the AH patients, an increase in the arterial stiffness index (ASI) is associated with an older age and an increase in systolic blood pressure (SBP); an increase in the augmentation index (AIx75) is associated with age; SBP in higher in women. Pulse wave velocity in the aorta (PWVao) is most associated with age, smoking, and family history in patients with hypertension and subclinical atherosclerosis. An increase in AIx75 is associated with an older age and is higher in women, while ASI has a positive relationship with age and SBP. In patients with hypertension and coronary artery disease, there is a positive correlation between male body mass index and PWVao. The increase in ASI in this group is associated with female gender, SBP and age. In individuals without hypertension and signs of atherosclerosis with a family history of CVD, PWVao values are higher than in similar individuals without a family history of CVD.&#x0D; CONCLUSIONS: In the group of all the participants, female gender, smoking, an older age, SBP, and body mass index are associated with increased AS parameters. The association between risk factors and parameters of arterial stiffness has peculiarities in patients with hypertension with varying degrees of severity of the atherosclerotic process.

Transgenically expressed Helicobacter pylori CagA in vascular endothelial cells accelerates arteriosclerosis in mice

Arteriosclerosis is intimately associated with cardiovascular diseases. Recently, evidence accumulated that infection with Helicobacter pylori cagA-positive strains, which causes gastritis, peptic ulceration, and gastric cancer, is also involved in the development of arteriosclerosis. The cagA-encoded CagA protein is injected into the attached gastric epithelial cells via the type IV secretion system. We previously showed that CagA-containing exosomes are secreted from CagA-injected gastric epithelial cells and enter the systemic blood circulation, delivering CagA into endothelial cells. In the present study, transgenic mice were established in which CagA was selectively expressed in endothelial cells by Cre-loxP system. Treatment of the mice with a high-fat diet revealed that atherogenic lesions were induced in mice expressing CagA in vascular endothelial cells but not in CagA-nonexpressing mice. To investigate the effects of CagA on endothelial cells, we also established conditional CagA-expressing human vascular endothelial cells using the Tet-on system. Upon induction of CagA, a dramatic change in cell morphology was observed that was concomitantly associated with the loss of the endothelial cells to form tube-like structures. Induction of CagA also activated the pro-inflammatory transcription factor STAT3. Thus, exosome-delivered CagA deregulates signals that activates STAT3 in endothelial cells, which accelerates inflammation that promotes arteriosclerosis/atherosclerosis.

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis.

Platelets play an important role in the pathogenesis of inflammatory and proliferative vascular changes. The aim of this study was to investigate whether human platelets are able to induce transplant arteriosclerosis in a humanized C57/Bl6-Rag2-/-γc-/- mouse xenograft model. Nonactivated and in vitro-activated human platelets were analyzed and phenotyped for surface markers by flow cytometry. Side branches of human mammary arteries were implanted into the infrarenal aorta of recipients, followed by daily application of human platelets and histological analyzed on day 30 after transplantation. Human platelets collected by apheresis had low levels of platelet activation markers. However, after in vitro activation, expression was markedly increased. Sixty minutes after injection in recipient mice, nonactivated human platelets become significantly activated. Increased adhesion of platelets to the vascular endothelium was detected by in vivo fluorescence microscopy. After intravenous injection of nonactivated or activated platelets, human xenografts showed pronounced intimal proliferation. Immunohistological analysis showed that the group treated with activated human platelets exhibited significantly increased intragraft protein expression of intracellular adhesion molecule-1 and platelet-derived growth factor receptor beta and smooth muscle cell migration into the neointima. These data demonstrate that an isolated daily application of both in vivo- and in vitro-activated human platelets results in the development of transplant arteriosclerosis in a humanized mouse transplantation model.

The Emerging Role of Rho Guanine Nucleotide Exchange Factors in Cardiovascular Disorders: Insights Into Atherosclerosis: A Mini Review.

Atherosclerosis is a leading cause of cardiovascular disease, and atherosclerotic cardiovascular disease accounts for one-third of global deaths. However, the mechanism of atherosclerosis is not fully understood. It is well-known that the Rho GTPase family, especially Rho A, plays a vital role in the development and progression of arteriosclerosis. Rho guanine nucleotide exchange factors (Rho GEFs), which act upstream of Rho GTPases, are also involved in the atheromatous pathological process. Despite some research on the role of Rho GEFS in the regulation of atherosclerosis, the number of studies is small relative to studies on the essential function of Rho GEFs. Some studies have preliminarily revealed Rho GEF regulation of atherosclerosis by experiments in vivo and in vitro. Herein, we review the advances in research on the relationship and interaction between Rho GEFs and atheroma to provide a potential reference for further study of atherosclerosis.

PostCOVID effect on endothelial function in hypertensive patients: A new research opportunity.

SARS‐CoV‐2 is causing devastation both in human lives and economic resources. When the world seems to start overcoming the pandemics scourge, the threat of long‐term complications of COVID‐19 is rising. Reports show that some of these long‐term effects may contribute to the main cause of morbimortality worldwide: the vascular diseases. Given the evidence of damage in the endothelial cells due to SARS‐CoV‐2 and that endothelial dysfunction precedes the development of arteriosclerosis, the authors propose to measure endothelial function around 6–12 months after acute disease in hypertensive patients, especially if they have other cardiovascular risk factors or overt vascular disease. The methods the authors propose are cost‐effective and can be made available to any hypertension unit. These methods could be the “in vivo” assessment of endothelial function by flow mediated vasodilatation after ischemia by Laser‐Doppler flowmetry and the measurement of plasma free circulating DNA and microparticles of endothelial origin.

Primary hypercholesterolemia and development of cardiovascular disorders: Cellular and molecular mechanisms involved in low-grade systemic inflammation and endothelial dysfunction.

Primary hypercholesterolemia, a metabolic disorder characterized by elevated circulating levels of cholesterol products, mainly low-density lipoproteins, is associated with arteriosclerosis development. Cardiovascular disease, predominantly myocardial infarction and stroke, remains the main cause of death worldwide, with atherosclerosis considered to be the most common underlying pathology. In addition to elevated plasma levels of low-density lipoproteins, low-grade systemic inflammation and endothelial dysfunction seem to be the main drivers of premature atherosclerosis. Here we review current knowledge related to cellular and molecular mechanisms involved in low-grade systemic inflammation and endothelial dysfunction associated with primary hypercholesterolemia. We also discuss the contribution of different inflammatory mediators, immune players and signaling pathways implicated in leukocyte adhesion to the dysfunctional endothelium, a key feature of atherogenesis development. A better understanding of these processes linked to primary hypercholesterolemia should shed new light on cardiovascular disease development and might guide novel and effective therapeutic strategies to impair its progression.

Polycyclic aromatic hydrocarbons induce endothelial injury through miR‐155 to promote atherosclerosis

Polycyclic aromatic hydrocarbons (PAHs) are considered as an external factor that induces atherosclerotic cardiovascular disease. Although miR-155 is known to be involved in cardiovascular disease, whether it is involved in PAH-induced arteriosclerosis remains unclear. We evaluated the effects of PAHs on vascularization, permeability, and miR-155 expression in HUVECs. We found that PAHs-induced sclerosis of HUVECs was characterized by increasing permeability, decreasing proliferation, and vascular lumen number. The expression of miR-155 was upregulated by PAHs treatment, and transfection with miR-155 inhibitor could reverse above effect of PAHs-induced sclerosis. Meanwhile, transcriptome sequencing revealed that 63 genes were downregulated in the group of PAHs treatment alone, and were then upregulated in the miR-155 inhibitor group. These genes were mainly involved in complement and coagulation cascades, cytokine-cytokine receptor interaction, TNF signaling pathway, and NF-kappa B signaling pathway. Among these 63 genes, SERPIND1 was directly targeted and regulated by miR-155. Further in vivo experiments in ApoE-/- mice confirmed that PAH accelerates the development of arteriosclerosis by promoting the expression of miR-155 to downregulate the SERPIND1. Therefore, PAH exaggerates atherosclerosis by activating miR-155-dependent endothelial injury. This study provides a fundamental insight on the miR-155 mechanism for PAHs enhancing atherosclerosis and miR-155 potentially serving as a novel drug target.

Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

Regulatory T Cells and the Effect of Ex Vivo Preservation on the Development of Transplant Arteriosclerosis in a Humanized Mouse Model

Regulatory T Cells and the Effect of Ex Vivo Preservation on the Development of Transplant Arteriosclerosis in a Humanized Mouse Model