Macrophages derived from LPS-stimulated monocytes from individuals with subclinical atherosclerosis were characterized by increased pro-inflammatory activity.

OBJECTIVE: Atherosclerosis is characterized by chronic inflammation in the vascular wall. Currently the violation of immune tolerance of innate immune cells is considered as a possible mechanism of chronification of inflammation. The aim of this study is to assess the inflammatory activity and tolerance of monocytes and macrophages in subclinical atherosclerosis. METHODS: A total of 55 individuals free from clinical manifestations of atherosclerosis-associated cardiovascular disease with a presence or absence of atherosclerotic plaques in the carotid arteries were included in this study. CD14+ monocytes were isolated from individuals' blood and stimulated with a single dose of lipopolysaccharide (LPS) on day 1 or with double doses of LPS on day 1 and day 6. The secretion of cytokines TNF, IL-1ß, IL-6, IL-8, IL-10 and CCL2 were evaluated using ELISA. RESULTS: Our findings demonstrate that macrophages derived from LPS-stimulated monocytes in individuals with subclinical atherosclerosis exhibited increased secretion of IL-6, IL-10 and CCL2, which was associated with intima-media thickness, body mass index, but not with individuals' age. Moreover, macrophages from individuals with atherosclerotic plaques exhibited impaired tolerance towards the second LPS stimulation manifested by elevated secretion of the chemoattractant CCL2. CONCLUSION: Increased secretion of these cytokines by macrophages may contribute to chronic local inflammation in the vascular wall by recruiting other immune cells.

Tumor Suppressor Properties of Small C-Terminal Domain Phosphatases in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) accounts for 80-90% of kidney cancers worldwide. Small C-terminal domain phosphatases CTDSP1, CTDSP2, and CTDSPL (also known as SCP1, 2, 3) are involved in the regulation of several important pathways associated with carcinogenesis. In various cancer types, these phosphatases may demonstrate either antitumor or oncogenic activity. Tumor-suppressive activity of these phosphatases in kidney cancer has been shown previously, but in general case, the antitumor activity may be dependent on the choice of cell line. In the present work, transfection of the Caki-1 cell line (ccRCC morphologic phenotype) with expression constructs containing the coding regions of these genes resulted in inhibition of cell growth in vitro in the case of CTDSP1 (p < 0.001) and CTDSPL (p < 0.05) but not CTDSP2. The analysis of The Cancer Genome Atlas (TCGA) data showed differential expression of some of CTDSP genes and of their target, RB1. These results were confirmed by quantitative RT-PCR using an independent sample of primary ccRCC tumors (n = 52). We observed CTDSPL downregulation and found a positive correlation of expression for two gene pairs: CTDSP1 and CTDSP2 (rs = 0.76; p < 0.001) and CTDSPL and RB1 (rs = 0.38; p < 0.05). Survival analysis based on TCGA data demonstrated a strong association of lower expression of CTDSP1, CTDSP2, CTDSPL, and RB1 with poor survival of ccRCC patients (p < 0.001). In addition, according to TCGA, CTDSP1, CTDSP2, and RB1 were differently expressed in two subtypes of ccRCC-ccA and ccB, characterized by different survival rates. These results confirm that CTDSP1 and CTDSPL have tumor suppressor properties in ccRCC and reflect their association with the more aggressive ccRCC phenotype.

Regulatory T Cells in Atherosclerosis: Is Adoptive Cell Therapy Possible?

Atherosclerosis is an insidious vascular disease with an asymptomatic debut and development over decades. The aetiology and pathogenesis of atherosclerosis are not completely clear. However, chronic inflammation and autoimmune reactions play a significant role in the natural course of atherosclerosis. The pathogenesis of atherosclerosis involves damage to the intima, immune cell recruitment and infiltration of cells such as monocytes/macrophages, neutrophils, and lymphocytes into the inner layer of vessel walls, and the accumulation of lipids, leading to vascular inflammation. The recruited immune cells mainly have a pro-atherogenic effect, whereas CD4+ regulatory T (Treg) cells are another heterogeneous group of cells with opposite functions that suppress the pathogenic immune responses. Present in low numbers in atherosclerotic plaques, Tregs serve a protective role, maintaining immune homeostasis and tolerance by suppressing pro-inflammatory immune cell subsets. Compelling experimental data suggest that various Treg cell-based approaches may be important in the treatment of atherosclerosis. Here we highlight the most recent advances in our understanding of the roles of FOXP3-expressing CD4+ Treg cells in the atherogenic process and discuss potential translational strategies for the treatment of atherosclerosis by Treg manipulation.

Mechanisms of the Wnt Pathways as a Potential Target Pathway in Atherosclerosis.

The proteins of the Wnt family are involved in a variety of physiological processes by means of several canonical and noncanonical signaling pathways. Wnt signaling has been recently identified as a major player in atherogenesis. In this review, we summarize the existing knowledge on the influence of various components of the Wnt signaling pathways on the initiation and progression of atherosclerosis and associated conditions. We used the PubMed database to search for recent papers on the involvement of the Wnt pathways in atherosclerosis. We used the combination of "Wnt" and "atherosclerosis" keywords to find the initial papers, and chose papers published after 2018. In the first section of the paper, we describe the general mechanisms of the Wnt signaling pathways and their components. The next section is dedicated to existing studies assessing the implication of Wnt signaling elements in different atherogenic processes, such as cholesterol retention, endothelial dysfunction, vascular inflammation, and atherosclerotic calcification of the vessels. Lastly, various therapeutic strategies based on interference with the Wnt signaling pathways are considered. We also compare the efficacy and availability of the proposed treatment methods. Wnt signaling can be considered a potential target in the treatment and prevention of atherosclerosis. Therefore, in this review, we reviewed evidences showing that wnt signaling is an important signal for developing appropriate treatment strategies for atherosclerosis.

Two Subpopulations of Human Monocytes That Differ by Mitochondrial Membrane Potential.

Atherosclerosis is associated with a chronic local inflammatory process in the arterial wall. Our previous studies have demonstrated the altered proinflammatory activity of circulating monocytes in patients with atherosclerosis. Moreover, atherosclerosis progression and monocyte proinflammatory activity were associated with mitochondrial DNA (mtDNA) mutations in circulating monocytes. The role of mitochondria in the immune system cells is currently well recognized. They can act as immunomodulators by releasing molecules associated with bacterial infection. We hypothesized that atherosclerosis can be associated with changes in the mitochondrial function of circulating monocytes. To test this hypothesis, we performed live staining of the mitochondria of CD14+ monocytes from healthy donors and atherosclerosis patients with MitoTracker Orange CMTMRos dye, which is sensitive to mitochondrial membrane potential. The intensity of such staining reflects mitochondrial functional activity. We found that parts of monocytes in the primary culture were characterized by low MitoTracker staining (MitoTracker-low monocytes). Such cells were morphologically similar to cells with normal staining and able to metabolize 5-aminolevulinic acid and accumulate the heme precursor protoporphyrin IX (PplX), indicative of partially preserved mitochondrial function. We assessed the proportion of MitoTracker-low monocytes in the primary culture for each study subject and compared the results with other parameters, such as monocyte ability to lipopolysaccharide (LPS)-induced proinflammatory activation and the intima-media thickness of carotid arteries. We found that the proportion of MitoTracker-low monocytes was associated with the presence of atherosclerotic plaques. An increased number of such monocytes in the primary culture was associated with a reduced proinflammatory activation ability of cells. The obtained results indicate the presence of circulating monocytes with mitochondrial dysfunction and the association of such cells with chronic inflammation and atherosclerosis development.

Lipid Metabolism in Macrophages: Focus on Atherosclerosis.

Mechanisms of lipid homeostasis and its impairment are of crucial importance for atherogenesis, and their understanding is necessary for successful development of new therapeutic approaches. In the arterial wall, macrophages play a prominent role in intracellular lipid accumulation, giving rise to foam cells that populate growing atherosclerotic plaques. Under normal conditions, macrophages are able to process substantial amounts of lipids and cholesterol without critical overload of the catabolic processes. However, in atherosclerosis, these pathways become inefficient, leading to imbalance in cholesterol and lipid metabolism and disruption of cellular functions. In this review, we summarize the existing knowledge on the involvement of macrophage lipid metabolism in atherosclerosis development, including both the results of recent studies and classical concepts, and provide a detailed description of these processes from the moment of lipid uptake with lipoproteins to cholesterol efflux.

Oxidative Stress and Antioxidants in Atherosclerosis Development and Treatment.

Atherosclerosis can be regarded as chronic inflammatory disease affecting the arterial wall. Despite the recent progress in studying the pathogenesis of atherosclerosis, some of the pathogenic mechanisms remain to be fully understood. Among these mechanisms is oxidative stress, which is closely linked to foam cells formation and other key events in atherosclerosis development. Two groups of enzymes are involved in the emergence of oxidative stress: Pro-oxidant (including NADPH oxidases, xanthine oxidases, and endothelial nitric oxide synthase) and antioxidant (such as superoxide dismutase, catalases, and thioredoxins). Pro-oxidant enzymes in normal conditions produce moderate concentrations of reactive oxidant species that play an important role in cell functioning and can be fully utilized by antioxidant enzymes. Under pathological conditions, activities of both pro-oxidant and antioxidant enzymes can be modified by numerous factors that can be relevant for developing novel therapies. Recent studies have explored potential therapeutic properties of antioxidant molecules that are capable to eliminate oxidative damage. However, the results of these studies remain controversial. Other perspective approach is to inhibit the activity of pro-oxidant enzymes and thus to slow down the progression of atherosclerosis. In this review we summarized the current knowledge on oxidative stress in atherosclerosis and potential antioxidant approaches. We discuss several important antioxidant molecules of plant origin that appear to be promising for treatment of atherosclerosis.

Contribution of Neurotrophins to the Immune System Regulation and Possible Connection to Alcohol Addiction.

The first references to neurotrophic factors date back to the middle of the 20th century when the nerve growth factor (NGF) was first discovered. Later studies delivered a large amount of data on neurotrophic factors. However, many questions regarding neurotrophin signaling still remain unanswered. One of the principal topics in neurotrophin research is their role in the immune system regulation. Another important research question is the possible involvement of neurotrophin signaling in the pathological processes associated with alcoholism. Among known neurotrophins, NT-4 remains the least studied and appears to be involved in alcoholism and chronic stress pathogenesis. In this review we discuss known neurotrophin signaling cascades mediated by different neurotrophin receptors, as well as provide a generalization of the data regarding the influence of neurotrophins NGF, BDNF, and NT-4 on the immune system and their potential contribution to the pathogenesis of alcoholism.

Comparative analysis of the variability of carotid intima-media thickness in primary prevention populations of Moscow and Paris.

Background: It is well-known that the distribution of traditional cardiovascular risk factors (CVRFs) of atherosclerosis, including hypertension, dyslipidemia, smoking, obesity, and diabetes is considerably variable between different countries, however, with some important geographical trends. Thus, CVRFs contribute differently to atherosclerosis development in different countries. Common carotid artery intima-media thickness (CCA IMT) is a validated biomarker of subclinical atherosclerosis that is used in clinical and epidemiological studies to evaluate the impact of CVRFs on atherosclerosis development. Material and methods: This comparative cohort study included a random sample of 1200 participants (n = 600 men and n = 600 women) from Moscow, Russia and Paris, France, aged between 55 and 79 years, and free of clinical symptoms of atherosclerosis. The study was conducted to determine the interpopulation variability of CCA IMT. CCA IMT was measured by ultrasonic scanning at the high-resolution regimen. Statistical analysis was performed using Stata 9.1. For comparison of mean values of continuous variables, Mann-Whitney U-test was used; Chi-square, Pearson's test was used for comparison of categorical variables. To determine to what extent presented differences can be explained by differences in traditional CVRFs, the regression model was applied. Path analysis (plug Passport Litigation Decision Analysis & Optimization Module, Datacert, USA) was used to assess the impact of traditional CVRFs on the CCA IMT in both Moscow and Paris study populations. Results: There was a significant difference in the distribution of most of the traditional CVRFs between the study populations, including blood pressure, lipid profile, statin treatment, hormone replacement therapy in women, and CVD history. The remarkably high level of difference in the mean values of the CCA IMT was found between Moscow and Paris study populations. In women of both Moscow and Paris study populations, the mean value of CCA IMT was 0.78 and 0.63, respectively. In men of both Moscow and Paris study populations, the mean CCA IMT value was 0.84 and 0.67, respectively. In the Moscow study population, the effects (direct and indirect) of traditional CVRs can explain 42% of the CCA IMT variance in women and 30% - in men. In the Paris study population, direct and indirect effects of traditional CVRFs can explain 27% of the CCA IMT variance in men and 14% - in women. Conclusion: The Paris study population significantly differed from the Moscow study population in the distribution and impact of traditional CVRFs. Traditional CVRFs can explain only a small proportion of the interpopulation differences in CCA IMT suggesting the presence of other factors, such as longitude, which can possibly influence these differences. Therefore, this study provided an additional piece of evidence towards the existence of a geographic gradient of carotid IMT.