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.

Condition "Vasa Vasorum" in Patients with Thoracic Aortic Aneurysm.

It is known that vasa vasorum contributes substantially to the blood supply and nutrition of one-third of the wall of the ascending thoracic aorta. Therefore, we focused on studying the relationship between inflammatory cells and vasa vasorum vessels in patients with aortic aneurysm. The material for the study was biopsies of thoracic aortic aneurysms taken from patients during an aneurysmectomy (34 men, 14 women, aged 33 to 79 years). The biopsies belonged to patients with non-hereditary thoracic aortic aneurysm. An immunohistochemical study was carried out using antibodies to antigens of T cells (CD3, CD4, CD8); macrophages (CD68); B cells (CD20); endothelium (CD31, CD34, von Willebrand factor (vWF)); and smooth muscle cells (alpha actin). Samples without inflammatory infiltrates contained less vasa vasorum in the tunica adventitia than samples with inflammatory infiltrates, and this difference was statistically significant p < 0.05. T cell infiltrates in the adventitia of aortic aneurysms were found in 28 of 48 patients. In the vessels of the vasa vasorum, surrounded by inflammatory infiltrates, T cells that adhered to the endothelium were found. The same cells were also localized in the subendothelial area. The number of adherent T cells in patients with inflammatory infiltrates in the aortic wall dominated the number of these cells in patients without inflammation of the aortic wall. This difference was statistically significant, p < 0.0006. Hypertrophy and sclerosis of the arteries of the vasa vasorum system, the narrowing of their lumen, and, as a result, impaired blood supply to the aortic wall, were found in 34 patients with hypertension. In 18 patients (both in patients with hypertension and in patients without hypertension), T cells that adhered to the vasa vasorum endothelium were found. In nine cases, massive infiltrates of T cells and macrophages were found, which surrounded and squeezed the vasa vasorum, preventing blood circulation. In six patients, parietal and obturating blood clots were found in the vasa vasorum vessels, which disrupted the normal blood supply to the aortic wall. We believe that this indicates the importance of the state of the vessels of the vasa vasorum in the development of an aortic aneurysm. In addition, pathological changes in these vessels may not always play a primary role, but always a very important role, in the pathogenesis of this disease.

Creation of Mitochondrial Disease Models Using Mitochondrial DNA Editing.

Mitochondrial diseases are a large class of human hereditary diseases, accompanied by the dysfunction of mitochondria and the disruption of cellular energy synthesis, that affect various tissues and organ systems. Mitochondrial DNA mutation-caused disorders are difficult to study because of the insufficient number of clinical cases and the challenges of creating appropriate models. There are many cellular models of mitochondrial diseases, but their application has a number of limitations. The most proper and promising models of mitochondrial diseases are animal models, which, unfortunately, are quite rare and more difficult to develop. The challenges mainly arise from the structural features of mitochondria, which complicate the genetic editing of mitochondrial DNA. This review is devoted to discussing animal models of human mitochondrial diseases and recently developed approaches used to create them. Furthermore, this review discusses mitochondrial diseases and studies of metabolic disorders caused by the mitochondrial DNA mutations underlying these diseases.

Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases.

Statins are competitive inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase and have been used to treat elevated low-density lipoprotein cholesterol (LDL-C) for almost four decades. Antioxidant and anti-inflammatory properties which are independent of the lipid-lowering effects of statins, i.e., their pleiotropic effects, might be beneficial in the prevention or treatment of many diseases. This review discusses the antioxidant effects of statins achieved by modulating the nuclear factor erythroid 2 related factor 2/ heme oxygenase-1 (Nrf2/HO-1) pathway in different organs and diseases. Nrf2 and other proteins involved in the Nrf2/HO-1 signaling pathway have a crucial role in cellular responses to oxidative stress, which is a risk factor for ASCVD. Statins can significantly increase the DNA-binding activity of Nrf2 and induce the expression of its target genes, such as HO-1 and glutathione peroxidase) GPx, (thus protecting the cells against oxidative stress. Antioxidant and anti-inflammatory properties of statins, which are independent of their lipid-lowering effects, could be partly explained by the modulation of the Nrf2/HO-1 pathway.

Mechanisms of antidiabetic drugs and cholesterol efflux: A clinical perspective.

Reverse cholesterol transport (RCT) is a physiological process that reduces excess cholesterol in the body. Cholesterol efflux (CE), an important step in RCT, is mainly mediated by ATP-binding cassette transporters A1 and G1 and has a significant role in atheroprotection. Moreover, impairments in CE can lead to the development of diabetes and fatty liver disease. In this review, we summarize the possible effects of hypoglycemic agents on CE and how this might influence atherosclerosis and dyslipidemia-related pathologies. Newer antidiabetic agents could have significant potential for targeting CE and preventing or alleviating atherosclerosis, obesity, and liver steatosis, and simultaneously improving insulin secretion. However, more research is warranted to interpret the clinical relevance of these data.

Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response.

The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells.