The Role of Cytokines in Cholesterol Accumulation in Cells and Atherosclerosis Progression.

Atherosclerosis is the most common cardiovascular disease and is the number one cause of death worldwide. Today, atherosclerosis is a multifactorial chronic inflammatory disease with an autoimmune component, accompanied by the accumulation of cholesterol in the vessel wall and the formation of atherosclerotic plaques, endothelial dysfunction, and chronic inflammation. In the process of accumulation of atherogenic lipids, cells of the immune system, such as monocytes, macrophages, dendritic cells, etc., play an important role, producing and/or activating the production of various cytokines-interferons, interleukins, chemokines. In this review, we have tried to summarize the most important cytokines involved in the processes of atherogenesis.

Target and Cell Therapy for Atherosclerosis and CVD.

Cardiovascular diseases (CVD) and, in particular, atherosclerosis, remain the main cause of death in the world today. Unfortunately, in most cases, CVD therapy begins after the onset of clinical symptoms and is aimed at eliminating them. In this regard, early pathogenetic therapy for CVD remains an urgent problem in modern science and healthcare. Cell therapy, aimed at eliminating tissue damage underlying the pathogenesis of some pathologies, including CVD, by replacing it with various cells, is of the greatest interest. Currently, cell therapy is the most actively developed and potentially the most effective treatment strategy for CVD associated with atherosclerosis. However, this type of therapy has some limitations. In this review, we have tried to summarize the main targets of cell therapy for CVD and atherosclerosis in particular based on the analysis using the PubMed and Scopus databases up to May 2023.

The Role of Adipokines in Inflammatory Mechanisms of Obesity.

Adipokines are currently widely studied cellular signaling proteins produced by adipose tissue and involved in various processes, including inflammation; energy and appetite modulation; lipid and glucose metabolism; insulin sensitivity; endothelial cell functioning; angiogenesis; the regulation of blood pressure; and hemostasis. The current review attempted to highlight the key functions of adipokines in the inflammatory mechanisms of obesity, its complications, and its associated diseases. An extensive search for materials on the role of adipokines in the pathogenesis of obesity was conducted online using the PubMed and Scopus databases until October 2022.

The Relationship between Mitochondrial Genome Mutations in Monocytes and the Development of Obesity and Coronary Heart Disease.

BACKGROUND: Metabolic disorders, including obesity, are often accompanied by an increased risk of cardiovascular complications. Monocytes are the common link between obesity and cardiovascular diseases (CVDs). The bias of innate cellular immunity towards pro-inflammatory activation stimulates the development of diseases associated with chronic inflammation, in particular metabolic disorders, including obesity, as well as CVDs. Disorders in the functional state of monocytes and activation of inflammation may be associated with mitochondrial dysfunction. Mutations accumulating in mitochondrial DNA with age may lead to mitochondrial dysfunction and may be considered a potential marker for developing chronic inflammatory diseases. METHODS: The present study aimed to study the relationship between mitochondrial heteroplasmy in CD14+ monocytes and cardiovascular risk factors in 22 patients with obesity and coronary heart disease (CHD) by comparing them to 22 healthy subjects. RESULTS: It was found that single-nucleotide variations (SNV) A11467G have a negative correlation with total cholesterol (r = -0.82, p < 0.05), low density lipoproteins (LDL) (r = -0.82, p < 0.05), with age (r = -0.57, p < 0.05) and with mean carotid intima-media thickness (cIMT) (r = -0.43, p < 0.05) and a positive correlation with HDL level (r = 0.71, p < 0.05). SNV 576insC positively correlated with body mass index (BMI) (r = 0.60, p < 0.001) and LDL level (r = 0.43, p < 0.05). SNV A1811G positively correlated with mean cIMT (r = 0.60, p < 0.05). CONCLUSIONS: It was revealed that some variants of mitochondrial DNA (mtDNA) heteroplasmy are associated with CVD risk factors. The results demonstrate the potential for using these molecular genetic markers to develop personalized CVD and metabolic disorder treatments.

Inflammatory Response of Monocytes/Macrophages in Patients with Systemic Sclerosis.

BACKGROUND: Investigation of the inflammatory response of immune cells is a current focus of research on autoimmune disorders. The aim of this study was to evaluate the inflammatory status of monocytes/macrophages in systemic sclerosis (SSc). METHODS: The study included 35 SSc and 25 healthy participants. The secretion of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA) in primary cultures of monocytes/macrophages after stimulation with lipopolysaccharide (LPS) on day 1 and on day 6 of incubation. Impaired tolerance of the immune response was characterized by increased secretion of the inflammatory mediators in response to restimulation. RESULTS: Basal secretion of all cytokines was significantly higher in SSc patients compared to healthy individuals. The secretion of TNF-α, IL-1ß and IL-6 after the initial LPS stimulation, and secretion of IL-1ß, MCP-1, IL-6, IL-8 after LPS restimulation, was significantly higher in the SSc group. Eleven SSc patients (31%) showed impaired immune tolerance in terms of MCP-1 secretion. These patients were significantly younger and had a higher level of anti-topoisomerase I (anti-Scl70) antibodies compared to SSc patients with immune tolerance. CONCLUSIONS: This study revealed pro-inflammatory activation and impaired immune tolerance in monocytes/macrophages from SSc patients. The violation of immune response in terms of MCP-1 secretion may be an important factor in the development of chronic inflammation in SSc. MCP-1 may thus be a potential therapeutic target for novel SSc treatment strategies.

Effect of LDL Extracted from Human Plasma on Membrane Stiffness in Living Endothelial Cells and Macrophages via Scanning Ion Conductance Microscopy.

Mechanical properties of living cells play a crucial role in a wide range of biological functions and pathologies, including atherosclerosis. We used low-stress Scanning Ion-Conductance Microscopy (SICM) correlated with confocal imaging and demonstrated the topographical changes and mechanical properties alterations in EA.hy926 and THP-1 exposed to LDL extracted from CVD patients' blood samples. We show that the cells stiffened in the presence of LDL, which also triggered caveolae formation. Endothelial cells accumulated less cholesterol in the form of lipid droplets in comparison to THP-1 cells based on fluorescence intensity data and biochemical analysis; however, the effect on Young's modulus is higher. The cell stiffness is closely connected to the distribution of lipid droplets along the z-axis. In conclusion, we show that the sensitivity of endothelial cells to LDL is higher compared to that of THP-1, triggering changes in the cytoskeleton and membrane stiffness which may result in the increased permeability of the intima layer due to loss of intercellular connections and adhesion.

The association of TNF-alpha secretion and mtDNA copy number in CD14+ monocytes of patients with obesity and CHD.

Introduction: Mitochondrial dysfunction may be one of the causes of inflammatory activation of monocytes and macrophages, which leads to excessive secretion of inflammatory mediators and the development of chronic inflammation. Aims: The study was aimed to evaluate the secretion of inflammatory cytokine tumor necrosis factor-α (TNF-α) in the primary culture of monocytes, and to analyze its relationship with the number of mitochondrial DNA (mtDNA) copies in the blood of patients with coronary heart disease (CHD) and obesity. Materials and methods: 108 patients with obesity and concomitant CHD and a control group of 25 participants were included in the study. CD14+ monocytes were isolated by a standard method in a ficoll-urographin gradient, followed by separation using magnetic particles. The number of mtDNA copies was estimated using qPCR. Results: It was demonstrated that the number of mtDNA copies was significantly increased in groups of patients with CHD and obesity + CHD in comparison with control group. mtDNA copy number positively correlated with basal and LPS-stimulated TNF-α secretion, the most significant correlation was found in the group of patients with CHD and obesity. Conclusion: Thus, the change in mtDNA copy number in CD14+ monocytes which indicates the presence of mitochondrial dysfunction, confirm the direct involvement of mitochondria in the violation of the inflammatory response of monocytes revealed in this study as an increased secretion of inflammatory cytokine TNF-α.

The Role of Macrophages in the Pathogenesis of Atherosclerosis.

A wide variety of cell populations, including both immune and endothelial cells, participate in the pathogenesis of atherosclerosis. Among these groups, macrophages deserve special attention because different populations of them can have completely different effects on atherogenesis and inflammation in atherosclerosis. In the current review, the significance of different phenotypes of macrophages in the progression or regression of atherosclerosis will be considered, including their ability to become the foam cells and the consequences of this event, as well as their ability to create a pro-inflammatory or anti-inflammatory medium at the site of atherosclerotic lesions as a result of cytokine production. In addition, several therapeutic strategies directed to the modulation of macrophage activity, which can serve as useful ideas for future drug developments, will be considered.

Mitochondrial DNA copy number in patients with systemic sclerosis.

Introduction: Systemic scleroderma (SSc) is a chronic autoimmune disease of inflammatory origin. Mitochondrial dysfunction is considered as an important mechanism in the pathogenesis of SSc. Currently mitochondrial DNA (mtDNA) copy number is used as a surrogate marker of mitochondrial dysfunction. Previous studies demonstrate that innate immune cells are important participants in inflammatory and fibrotic processes in SSc. The aim of the study was to evaluate the number of mtDNA copies in CD14+ monocytes and whole blood of patients with SSc in comparison with healthy individuals. Methods: Absolute mtDNA copy number was measured using digital PCR. It was found that the number of mtDNA copies in CD14+ monocytes was significantly higher in patients with SSc compared to control, while the number of mtDNA copies in the whole blood did not have significant differences. Results: The correlation analysis revealed an inverse association of mtDNA copy number with disease duration and the relationship between pro-inflammatory activation of CD14+ monocytes in terms of LPS-stimulated IL-6 secretion and mtDNA copy number. At the same time, basal and LPS-stimulated secretion of IL-6 by cultured CD+ monocytes were significantly higher in SSc group in comparison with control. Discussion: The study results suggest that increase of mtDNA copy number in CD14+ monocytes is a possible mechanism to maintain the reduced function of defective mitochondria in monocytes from patients with SSc associated with the development and progression of SSc.

Disturbance of Mitochondrial Dynamics and Mitochondrial Therapies in Atherosclerosis.

Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death-features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.