Different Approaches in Therapy Aiming to Stabilize An Unstable Atherosclerotic Plaque

Atherosclerotic plaque vulnerability is a vital clinical problem as vulnerable plaques tend to rupture, which results in atherosclerosis complications—myocardial infarctions and subsequent cardiovascular deaths. Therefore, methods aiming to stabilize such plaques are in great demand. In this brief review, the idea of atherosclerotic plaque stabilization and five main approaches—towards the regulation of metabolism, macrophages and cellular death, inflammation, reactive oxygen species, and extracellular matrix remodeling have been presented. Moreover, apart from classical approaches (targeted at the general mechanisms of plaque destabilization), there are also alternative approaches targeted either at certain plaques which have just become vulnerable or targeted at the minimization of the consequences of atherosclerotic plaque erosion or rupture. These alternative approaches have also been briefly mentioned in this review.

From Mitochondria to Atherosclerosis: The Inflammation Path

Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable atherosclerotic plaque rupture causing platelet aggregation and thrombosis may compromise the arterial lumen, leading to acute or chronic ischemic syndromes. In this review, we will focus on the role of mitochondria in atherosclerosis while keeping inflammation as a link. Mitochondria are the main source of cellular energy. Under stress, mitochondria are also capable of controlling inflammation through the production of reactive oxygen species (ROS) and the release of mitochondrial components, such as mitochondrial DNA (mtDNA), into the cytoplasm or into the extracellular matrix, where they act as danger signals when recognized by innate immune receptors. Primary or secondary mitochondrial dysfunctions are associated with the initiation and progression of atherosclerosis by elevating the production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments.

The Study of Biochemical Factors of Calcification of Stable and Unstable Plaques in the Coronary Arteries of Man

Objective. The aim of the study was to study biochemical factors of calcification in stable and unstable plaques of coronary arteries and in the blood of patients with severe coronary atherosclerosis, to find associations of biochemical factors of calcification with the development of unstable atherosclerotic plaque.Materials and Methods. The study included 25 men aged 60,4±6,8 years who received coronary bypass surgery. In the course of the operation intraoperative indications in men were from coronary endarteriectomy (s) artery (a – d) and histological and biochemical analyses of the samples of the intima / media. Out of 85 fragments of intima / media of coronary arteries, 15 fragments of unchanged intima / media, 39 fragments of stable atheromatous plaque and 31 fragments of unstable plaque were determined. In homogenates of samples of intima / media (after measurement of protein by the method of Lowry) and in blood by ELISA were determined by biochemical factors of calcification: osteoprotegerin, osteocalcin, an osteopontin, osteonectin, as well as inflammatory factors (cytokines, chemokines).Results. A significant direct correlation (Spearman coefficient =0.607, p<0.01) between the stages of atherosclerotic focus development to unstable plaque and the degree of calcification of atherosclerotic focus development samples was found. There was an increased content of osteocalcin in stable and unstable plaques by 3.3 times in comparison with the unchanged tissue of intima / media of coronary arteries, as well as in samples with small and dust-like, with coarse-grained calcifications in comparison with samples without calcifications by 2.8 and 2.1 times, respectively. According to multivariate logistic regression analysis, the relative risk of unstable atherosclerotic plaque in the coronary artery is associated with a reduced content of osteocalcin (OR=0.988, 95 % CI 0.978–0.999, p=0.028). Also, the relative risk of calcifications in the atherosclerotic plaque in the coronary artery is associated with an increased content of osteocalcin (OR=1,008, 95 % CI 1,001–1,015, p=0,035). In men with severe coronary atherosclerosis, a significant inverse correlation was found (Spearman coefficient –0.386, p=0.022) between the content of osteoprotegerin in the vascular wall and in the blood.

Novel Plaque Enriched Long Noncoding RNA in Atherosclerotic Macrophage Regulation (PELATON)

Objective: Long noncoding RNAs (lncRNAs) are an emergent class of molecules with diverse functional roles, widely expressed in human physiology and disease. Although some lncRNAs have been identified in cardiovascular disease, their potential as novel targets in the prevention of atherosclerosis is unknown. We set out to discover important lncRNAs in unstable plaque and gain insight into their functional relevance. Approach and Results: Analysis of RNA sequencing previously performed on stable and unstable atherosclerotic plaque identified a panel of 47 differentially regulated lncRNAs. We focused on LINC01272, a lncRNA upregulated in unstable plaque previously detected in inflammatory bowel disease, which we termed PELATON (plaque enriched lncRNA in atherosclerotic and inflammatory bowel macrophage regulation). Here, we demonstrate that PELATON is highly monocyte- and macrophage-specific across vascular cell types, and almost entirely nuclear by cellular fractionation (90%–98%). In situ hybridization confirmed enrichment of PELATON in areas of plaque inflammation, colocalizing with macrophages around the shoulders and necrotic core of human plaque sections. Consistent with its nuclear localization, and despite containing a predicted open reading frame, PELATON did not demonstrate any protein-coding potential in vitro. Functionally, knockdown of PELATON significantly reduced phagocytosis, lipid uptake and reactive oxygen species production in high-content analysis, with a significant reduction in phagocytosis independently validated. Furthermore, CD36, a key mediator of phagocytic oxLDL (oxidized low-density lipoprotein) uptake was significantly reduced with PELATON knockdown. Conclusions: PELATON is a nuclear expressed, monocyte- and macrophage-specific lncRNA, upregulated in unstable atherosclerotic plaque. Knockdown of PELATON affects cellular functions associated with plaque progression.

Comparative immunohistochemical and morphometric research of interleukin-17 in various atherosclerotic lesions in human

The aim of the artical to investigate cellular and tissue localization of IL-17 in various atherosclerotic lesions of arteries of human and on the basis of the obtained data to make a hypothesis of a possible role of Th-17 of cells in destabilization of an atherosclerotic plaque. Material and methods. On autopsy material by means of histologic, immunohistochemical and morphometric research techniques aorta segments, the coronary arteries and a.basilaris with various types of atherosclerotic lesions (43 samples of tissue) were studied. In samples of tissue studied the endothelial and mononuclear cells expressing interleukin-17. Results. It is shown that endothelial cells of an intima are capable to produce IL-17 in all types of atherosclerotic plaques. Increase in number of the mononuclear cells expressing IL-17 in an intima of arteries was at the same time revealed. It is shown that the maximum number of the cells expressing IL-17 was found in an intima of an unstable atherosclerotic plaque, it is especially frequent around a rupture of its cap. What can demonstrate pro-inflammatory action of Th - 17 - cells and IL-17 expressed by them and significant effect them on formation of unstable atherosclerotic lesions. Conclusion. On the basis of the obtained data for the first time it was succeeded to make a hypothesis of a possible role of Th-17 of cells in destabilization of an atherosclerotic plaque.

A New Strategy for the Treatment of Atherothrombosis – Inhibition of Inflammation

Improvement in the prognosis of patients at risk of atherothrombotic events is based on three pillars – slowing down the process of atherogenesis (i.e. the development of atherosclerotic plaque), stabilizing the current atherosclerotic plaque, and reducing the risk of thrombotic occlusion in cases with unstable atherosclerotic plaque. The current prophylaxis has so far taken into consideration the adjustment of several risk factors, including dyslipidemia, arterial hypertension, smoking, and diabetes through lifestyle changes or pharmacological therapies. An essential part of prophylaxis is the anti-thrombotic strategy, especially anti-platelet therapy. Recently, a new pathway has been developed, based on reducing the activity of the inflammatory process with NLRP3 inflammasome, specifically a monoclonal antibody against interleukin 1β (canakinumab). The efficacy and safety of this treatment, in secondary prevention, were documented in the CANTOS study. Other therapeutic procedures, including suppression of the inflammatory component of atherogenesis, are at the stage of clinical assessment.