Oxidative Stress In Atherosclerosis Research Articles

The relationship of redox signaling with the risk for atherosclerosis.

Oxidative balance plays a pivotal role in physiological homeostasis, and many diseases, particularly age-related conditions, are closely associated with oxidative imbalance. While the strategic role of oxidative regulation in various diseases is well-established, the specific involvement of oxidative stress in atherosclerosis remains elusive. Atherosclerosis is a chronic inflammatory disorder characterized by plaque formation within the arteries. Alterations in the oxidative status of vascular tissues are linked to the onset, progression, and outcome of atherosclerosis. This review examines the role of redox signaling in atherosclerosis, including its impact on risk factors such as dyslipidemia, hyperglycemia, inflammation, and unhealthy lifestyle, along with dysregulation, vascular homeostasis, immune system interaction, and therapeutic considerations. Understanding redox signal transduction and the regulation of redox signaling will offer valuable insights into the pathogenesis of atherosclerosis and guide the development of novel therapeutic strategies.

Treatment with PCSK9 Inhibitor Evolocumab Improves Vascular Oxidative Stress and Arterial Stiffness in Hypercholesterolemic Patients with High Cardiovascular Risk.

Atherosclerosis and atherosclerotic-related cardiovascular diseases (ASCVD) are characterized by high serum levels of low-density lipoprotein cholesterol (LDL-C) that can promote the generation of reactive oxygen species (ROS). To answer the need for better LDL-C control in individuals at high and very high risk for CVD, a new injectable innovative family of lipid-lowering (LL) monoclonal antibodies against the protein convertase subtilisin/kexin type 9 (PCSK9) has been approved. However, the effect of these drugs on vascular function, such as ROS generation and arterial stiffness, has not already been extensively described. In this report, we present data from 18 males with high to very high CV risk undergoing LL treatment (LLT) with either statin and ezetimibe or ezetimibe monotherapy, who experienced, after a 2-month treatment with Evolocumab, a significant improvement in blood pressure (BP)-adjusted carotid-femoral pulse wave velocity (cfPWV) (p-value = 0.0005 in the whole cohort, p-value = 0.0046 in the sub-cohort undergoing background LLT with statin and ezetimibe, p-value = 0.015 in the sub-cohort undergoing background LLT with ezetimibe monotherapy), which was significantly associated with a decrease in freshly isolated leukocytes (PBMCS)-derived H2O2 production (p-value = 0.004, p-value = 0.02 and p-value = 0.05, respectively, in the whole cohort, in the statin + ezetimibe sub-cohort, and the ezetimibe sub-cohort). Our observations support the role of systemic oxidative stress in atherosclerosis and give a further rationale for using Evolocumab also for its effect in vascular disorders linked to oxidative processes.

Oxidative Stress Modulation by ncRNAs and Their Emerging Role as Therapeutic Targets in Atherosclerosis and Non-Alcoholic Fatty Liver Disease.

Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are pathologies related to ectopic fat accumulation, both of which are continuously increasing in prevalence. These threats are prompting researchers to develop effective therapies for their clinical management. One of the common pathophysiological alterations that underlies both diseases is oxidative stress (OxS), which appears as a result of lipid deposition in affected tissues. However, the molecular mechanisms that lead to OxS generation are different in each disease. Non-coding RNAs (ncRNAs) are RNA transcripts that do not encode proteins and function by regulating gene expression. In recent years, the involvement of ncRNAs in OxS modulation has become more recognized. This review summarizes the most recent advances regarding ncRNA-mediated regulation of OxS in atherosclerosis and NAFLD. In both diseases, ncRNAs can exert pro-oxidant or antioxidant functions by regulating gene targets and even other ncRNAs, positioning them as potential therapeutic targets. Interestingly, both diseases have common altered ncRNAs, suggesting that the same molecule can be targeted simultaneously when both diseases coexist. Finally, since some ncRNAs have already been used as therapeutic agents, their roles as potential drugs for the clinical management of atherosclerosis and NAFLD are analyzed.

The Role of Oxidative Stress in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.

RhoA/ROCK-1 Signaling Pathway and Oxidative Stress in Coronary Artery Disease Patients.

IntroductionCoronary artery disease (CAD) is an ischemic condition that occurs as a result of partial or complete interruption of blood flow by narrowing or complete blockage of the vessels supplying the heart, which are called coronary arteries. Our objective in this study is to investigate the RhoA/Rho-associated kinase (ROCK)-1 signaling pathway and oxidative stress in CAD patients.MethodsA total of 81 individuals aged between 40-70 years - including 45 patients (15 females and 30 males) who were admitted to the Artvin State Hospital Cardiovascular Surgery Clinic and were diagnosed with CAD and 36 healthy volunteers (15 females and 21 males) - participated in this study. Serum samples were tested for total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, malondialdehyde (MDA), superoxide dismutase (SOD), RhoA, and ROCK-1 values.ResultsSerum RhoA, MDA levels, and ROCK-1 activity in the CAD group were found to be statistically significantly higher than in the control group (P<0.001). Concordantly, serum SOD activity was found to be statistically significantly lower in the CAD group than in the control group (P<0.001).ConclusionInhibition of the activity of RhoA/ROCK-1 pathway would be beneficial in treating cardiovascular diseases since this pathway plays an important role in the development of these diseases.

Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress.

Atherosclerosis remains the underlying process responsible for cardiovascular diseases and the high mortality rates associated. This chronic inflammatory disease progresses with the formation of occlusive atherosclerotic plaques over the inner walls of vascular vessels, with oxidative stress being an important element of this pathology. Oxidation of low-density lipoproteins (ox-LDL) induces endothelial dysfunction, foam cell activation, and inflammatory response, resulting in the formation of fatty streaks in the atherosclerotic wall. With this in mind, different approaches aim to reduce oxidative damage as a strategy to tackle the progression of atherosclerosis. Special attention has been paid in recent years to the transcription factor Nrf2 and its downstream-regulated protein heme oxygenase-1 (HO-1), both known to provide protection against atherosclerotic injury. In the current review, we summarize the involvement of oxidative stress in atherosclerosis, focusing on the role that these antioxidant molecules exert, as well as the potential therapeutic strategies applied to enhance their antioxidant and antiatherogenic properties.

Trimetazidine Therapy in Coronary Artery Disease: The Impact on Oxidative Stress, Inflammation, Endothelial Dysfunction, and Long-Term Prognosis.

In coronary artery disease (CAD), reduction of perfusion in coronary arteries is followed by increases of oxidative stress and decreases of adenosine triphosphate reserve. In this condition, trimetazidine (TMZ), a metabolic anti-ischemic agent, seems to be an ideal therapeutic agent because it increases mitochondrial adenosine triphosphate production. To evaluate the impact of TMZ on oxidative stress, inflammation, endothelial dysfunction, and long-term prognosis in CAD. Patients with CAD with symptoms not adequately controlled were enrolled consecutively for a period of 18 months. Five hundred seventy patients with CAD were enrolled in a prospective study and divided into 4 groups in relation with the type of CAD and the addition of TMZ to optimal medical therapy (OMT). The impact of TMZ added to OMT on oxidative stress (total antioxidant status, antioxidized low-density lipoprotein antibodies, and antimyeloperoxidase antibodies), endothelial dysfunction (flow-mediated dilatation and von Willebrand factor activity), and inflammation (C-reactive protein and fibrinogen) at 6 months and on long-term prognosis in CAD in comparison with OMT at 5 years of follow-up was evaluated. At 6 months, TMZ added to OMT significantly decreased the incidence of oxidative stress in CAD (P < 0.03) and reduced endothelial dysfunction and inflammation only in non-ST-elevation acute coronary syndrome (NSTE-ACS, P < 0.04). TMZ added to OMT with or without interventional/surgical vascularization led to decreased readmission for NSTE-ACS and heart failure (P < 0.05) in all patients with CAD and a significantly reduced incidence of cardiovascular death, acute myocardial infarction, and stroke (P < 0.05) in patients with NSTE-ACS at 5 years of follow-up. In patients with NSTE-ACS, TMZ added to OMT with or without interventional and/or surgical reperfusion reduced oxidative stress, endothelial dysfunction, inflammation, and major acute cardiovascular events, whereas in patients with chronic coronary syndrome, TMZ decreased oxidative stress and readmission for ACS and heart failure.

Chinese Herbal Medicines and Active Metabolites: Potential Antioxidant Treatments for Atherosclerosis.

Atherosclerosis is a complex chronic disease that occurs in the arterial wall. Oxidative stress plays a crucial role in the occurrence and progression of atherosclerotic plaques. The dominance of oxidative stress over antioxidative capacity generates excess reactive oxygen species, leading to dysfunctions of the endothelium and accelerating atherosclerotic plaque progression. Studies showed that Chinese herbal medicines and traditional Chinese medicine (TCM) might regulate oxidative stress; they have already been used to treat diseases related to atherosclerosis, including stroke and myocardial infarction. This review will summarize the mechanisms of oxidative stress in atherosclerosis and discuss studies of Chinese herbal medicines and TCM preparations treating atherosclerosis, aiming to increase understanding of TCM and stimulate research for new drugs to treat diseases associated with oxidative stress.

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.

Effect on MicroRNA-92a in Atherosclerosis along with FlowMediated Vasodilation Study

Atherosclerosis has been regarded as an inflammatory disease. The vascular endothelium is considered as having multiple functions, regulating vascular tone, thrombosis, haematosis, permeability and cell adhesion. The emergence of microRNAs (miRNAs) as significant regulators of pathophysiological processes has indicated novel molecular insights and provided new therapeutic targets in atherosclerotic condition. Many studies have revealed that miRNA are associated with cardiovascular disease (CVD). With respect to miR-92a, miR -92a, a member of the miR-17 to miR-92 cluster, is expressed highly in endothelial cells (ECs) and regulated by shear stress. Both In vitro and vivo, miR-92a expression is highly induced in atheroprone regions compared with atheroresistant regions under disturbed flow (d-flow) condition. The clinical and experimental studies have suggested that inhibition of miR-92a can contribute to the improvement of endothelial dysfunction, inflammation, and oxidative stress in atherosclerosis. Recent reports showed that antimiR-92a as novel therapeutic options can be attributed to the endothelial cell autophagy and cardiomyocyte metabolism and that mechanistically, atherosclerotic status promote the packaging of functional miR-92a-3p into endothelial microvesicles, thereby promoting angiogenic response into recipient endothelial cells. It is strongly suggested that miR-92a-3p, having novel biological function and mechanism is a potent therapeutic target in atherosclerosis-related diseases. It is putative that flow-mediated vasodilation (FMD) study, early surrogate marker of endothelial function may in part reflect miR-92a, multifunctional biomarker

Effects of Selected Antioxidants on Atherosclerosis in Hyperlipidemic Wistar Rats

The interplay of hyperlipidemia and oxidative stress in atherosclerosis has been fairly established by previous studies. There remains however, paucity of data in this environment on the direct effects of antioxidants on atherosclerosis. This study therefore aimed at determining the protective effects of EDTA, vitamin C and Vitamin E on atherosclerosis in diet induced heperlipidemic wister rats.&#x0D; Thirty Wister rats were investigated in this study. The rats were randomly divided into five groups (n=6). The control group was fed with growers mash and water only while group II-V were induced with hyperlipidemic diet for ten weeks. In addition to the hyperlipidemic diet; group III received 1 g/kg body weight of EDTA, group IV received 1 g/kg body weight of vitamin C, group V received 1 g/kg body weight of vitamin E, and group VI received EDTA, vitamin C and E. The group’s treatments were orally for two weeks. C-reactive protein, Total cholesterol (TC), Triglyceride (TG), HDL-cholesterol, LDL-cholesterol, Total calcium and Total antioxidant status were analyzed using standard methods after the treatments.&#x0D; The study showed significant effect in the use of EDTA, Vitamin C and Vitamin E in the treatment of atherosclerosis in rats which could be due to their antioxidant and anti-hyperlipidemic properties. Therefore the combinations EDTA, vitamin C and vitamin E appear greatly protective against atherosclerosis.

Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis.

Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.

LOX-1: Regulation, Signaling and Its Role in Atherosclerosis.

Atherosclerosis has long been known to be a chronic inflammatory disease. In addition, there is intense oxidative stress in atherosclerosis resulting from an imbalance between the excess reactive oxygen species (ROS) generation and inadequate anti-oxidant defense forces. The excess of the oxidative forces results in the conversion of low-density lipoproteins (LDL) to oxidized LDL (ox-LDL), which is highly atherogenic. The sub-endothelial deposition of ox-LDL, formation of foamy macrophages, vascular smooth muscle cell (VSMC) proliferation and migration, and deposition of collagen are central pathophysiologic steps in the formation of atherosclerotic plaque. Ox-LDL exerts its action through several different scavenger receptors, the most important of which is LOX-1 in atherogenesis. LOX-1 is a transmembrane glycoprotein that binds to and internalizes ox-LDL. This interaction results in variable downstream effects based on the cell type. In endothelial cells, there is an increased expression of cellular adhesion molecules, resulting in the increased attachment and migration of inflammatory cells to intima, followed by their differentiation into macrophages. There is also a worsening endothelial dysfunction due to the increased production of vasoconstrictors, increased ROS, and depletion of endothelial nitric oxide (NO). In the macrophages and VSMCs, ox-LDL causes further upregulation of the LOX-1 gene, modulation of calpains, macrophage migration, VSMC proliferation and foam cell formation. Soluble LOX-1 (sLOX-1), a fragment of the main LOX-1 molecule, is being investigated as a diagnostic marker because it has been shown to be present in increased quantities in patients with hypertension, diabetes, metabolic syndrome and coronary artery disease. LOX-1 gene deletion in mice and anti-LOX-1 therapy has been shown to decrease inflammation, oxidative stress and atherosclerosis. LOX-1 deletion also results in damage from ischemia, making LOX-1 a promising target of therapy for atherosclerosis and related disorders. In this article we focus on the different mechanisms for regulation, signaling and the various effects of LOX-1 in contributing to atherosclerosis.

IDENTIFICATION OF NOVEL MICRORNAS ASSOCIATED ATHEROSCLEROTIC LESION FORMATION IN THE AORTA OF HYPERCHOLESTEROLEMIC APOE-/- MICE

Objective: Evidence is accumulating that microRNAs (miRNAs), members of the non-coding RNA family, may be effective biomarkers and therapeutic targets in atherosclerosis. The aim of this study was to identify novel miRNA expression patterns underlying vascular inflammation and oxidative stress associated with atheroma formation in human and experimental atherosclerosis. Design and method: Human non-atherosclerotic (superior thyroid artery) and atherosclerotic (carotid artery) arterial specimens, ApoE-/- mice, and in vitro polarized pro-, and anti-inflammatory mouse macrophages (Mac) were used. Male ApoE-/- mice were maintained on normal (ND) or high-fat cholesterol rich (HD) diet for 6 months to accelerate de development of advanced atherosclerotic lesions along the aorta. Atherosclerotic lesions were analyzed by Oil Red O staining and immunohistochemistry (markers of immune cell infiltration, CD45, CD68). Human and mouse miRCURY LNA™ miRNome real-time PCR panels were employed to determine the expression pattern of 752 different miRNAs. Microarray-based (Agilent SurePrint G3 Human/Mouse gene Expression v2 8x60K) genome-wide gene expression profiling was done to determine the ratio between a specific miRNA and the expression level of its predicted mRNA target. miRNA target prediction tools were used (miRanda, MiRBase, miRWalk, Target Scan, etc). Results: miRNA expression profiling revealed that 272 miRNAs are significantly up-regulated and 224 down-regulated in the atherosclerotic aorta of ApoE-/- (HD) mice as compared to values obtained for ApoE-/- (ND) animals. A cluster of 49 miRNAs with upregulated levels in atherosclerotic aorta of mice were detected in cultured pro-inflammatory mouse Mac as compared to resting Mac. In cultured anti-inflammatory Mac, the augmented expression of 63 miRNA was detected. Similarly regulated (up/down) homologous miRNAs were determined in both human and mouse atherosclerotic tissues. Candidate miRNAs linked to vascular inflammation and oxidative stress in atherosclerosis were predicted by in silico analysis. Conclusions: We found new miRNA panels reporting information about key pathological processes linked to atheroma formation such as inflammation and oxidative stress in both human and experimental atherosclerosis. The data of this study point to the novel atherosclerotic tissue-expressed miRNAs as potential biomarkers and/or therapeutic targets in atherosclerosis-related cardiovascular disorders.

The effects of oxidative stress on the development of atherosclerosis.

Atherosclerosis is a cardiovascular disease (CVD) known widely world wide. Several hypothesizes are suggested to be involved in the narrowing of arteries during process of atherogenesis. The oxidative modification hypothesis is related to oxidative and anti-oxidative imbalance and is the most investigated. The aim of this study was to review the role of oxidative stress in atherosclerosis. Furthermore, it describes the roles of oxidative/anti-oxidative enzymes and compounds in the macromolecular and lipoprotein modifications and in triggering inflammatory events. The reactive oxygen (ROS) and reactive nitrogen species (RNS) are the most important endogenous sources produced by non-enzymatic and enzymatic [myeloperoxidase (MPO), nicotinamide adenine dinucleotide phosphate (NADH) oxidase and lipoxygenase (LO)] reactions that may be balanced with anti-oxidative compounds [glutathione (GSH), polyphenols and vitamins] and enzymes [glutathione peroxidase (Gpx), peroxiredoxins (Prdx), superoxide dismutase (SOD) and paraoxonase (PON)]. However, the oxidative and anti-oxidative imbalance causes the involvement of cellular proliferation and migration signaling pathways and macrophage polarization leads to the formation of atherogenic plaques. On the other hand, the immune occurrences and the changes in extra cellular matrix remodeling can develop atherosclerosis process.

Vasculoprotective Role of Olive Oil Compounds via Modulation of Oxidative Stress in Atherosclerosis.

Existing evidence supports the significant role of oxidative stress in the endothelial injury, and there is a direct link between increased oxidative stress, and the development of endothelial dysfunction. Endothelial dysfunction precedes the development of atherosclerosis and subsequent cardiovascular disease (CVD). The overproduction of reactive oxygen species facilitates the processes, such as oxidative modification of low-density lipoproteins and phospholipids, reduction in the NOS-derived nitric oxide, and the functional disruption of high-density lipids that are profoundly involved in atherogenesis, inflammation, and thrombus formation in vascular cells. Thus, under oxidative stress conditions, endothelial dysfunction was found to be associated with the following endothelial alterations: reduced nitric oxide bioavailability, increased anticoagulant properties, increased platelet aggregation, increased expression of adhesion molecules, chemokines, and cytokines. In this review, we summarized the evidence indicating that endothelial damage triggered by oxidation can be diminished or reversed by the compounds of olive oil, a readily available antioxidant food source. Olive oil bioactive compounds exhibited a potent capability to attenuate oxidative stress and improve endothelial function through their anti-inflammatory, anti-oxidant, and anti-thrombotic properties, therefore reducing the risk and progression of atherosclerosis. Also, their molecular mechanisms of action were explored to establish the potential preventive and/or therapeutic alternatives to the pharmacological remedies available.

Structural analysis of a Petri net model of oxidative stress in atherosclerosis.

Atherosclerosis is a complex process of gathering sub-endothelial plaques decreasing lumen of the blood vessels. This disorder affects people of all ages, but its progression is asymptomatic for many years. It is regulated by many typical and atypical factors including the immune system response, a chronic kidney disease, a diet rich in lipids, a local inflammatory process and a local oxidative stress that is here one of the key factors. In this study, a Petri net model of atherosclerosis regulation is presented. This model includes also some information about stoichiometric relationships between its components and covers all mentioned factors. For the model, a structural analysis based on invariants was made and biological conclusions are presented. Since the model contains inhibitor arcs, a heuristic method for analysis of such cases is presented. This method can be used to extend the concept of feasible t-invariants.

Oxidative Stress in Atherosclerosis.

Atherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury. Endogenous anti-oxidants function as checkpoints to avoid these untoward consequences of ROS, and an imbalance in the oxidant/anti-oxidant mechanisms leads to a state of oxidative stress. In this review, we discuss the role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and highlight potential anti-oxidant therapeutic strategies relevant to atherosclerosis. There is growing evidence on how traditional risk factors translate into oxidative stress and contribute to atherosclerosis. Clinical trials evaluating anti-oxidant supplements had failed to improve atherosclerosis. Current studies focus on newer ROS scavengers that specifically target mitochondrial ROS, newer nanotechnology-based drug delivery systems, gene therapies, and anti-miRNAs. Synthetic LOX-1 modulators that inhibit the effects of Ox-LDL are currently in development. Research over the past few decades has led to identification of multiple ROS generating systems that could potentially be modulated in atherosclerosis. Therapeutic approaches currently being used for atheroslcerotic vascular disease such as aspirin, statins, and renin-angiotensin system inhibitors exert a pleiotropic antioxidative effects. There is ongoing research to identify novel therapeutic modalities to selectively target oxidative stress in atherosclerosis.

Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies.

Atherogenesis, the formation of atherosclerotic plaques, is a complex process that involves several mechanisms, including endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis. The pathogenesis and progression of atherosclerosis are explained differently by different scholars. One of the most common theories is the destruction of well-balanced homeostatic mechanisms, which incurs the oxidative stress. And oxidative stress is widely regarded as the redox status realized when an imbalance exists between antioxidant capability and activity species including reactive oxygen (ROS), nitrogen (RNS) and halogen species, non-radical as well as free radical species. This occurrence results in cell injury due to direct oxidation of cellular protein, lipid, and DNA or via cell death signaling pathways responsible for accelerating atherogenesis. This paper discusses inflammation, mitochondria, autophagy, apoptosis, and epigenetics as they induce oxidative stress in atherosclerosis, as well as various treatments for antioxidative stress that may prevent atherosclerosis.

ИТОГИ ИЗУЧЕНИЯ ПАТОФИЗИОЛОГИЧЕСКИХ ПОСЛЕДСТВИЙ НАРУШЕНИЯ РЕГУЛЯЦИИ СВОБОДНОРАДИКАЛЬНЫХ ПРОЦЕССОВ: ТУПИК ИЛИ НОВЫЙ ИМПУЛЬС?

The review presents the results of the authors' work of many years and the data of foreign studies, indicating the importance of free radical processes in etiology and pathogenesis of atherosclerosis. The justification of the idea that oxidative stress in atherosclerosis develops more often during disorders of carbohydrate metabolism, contributing to emergence of carbonyl stress in diabetes. It is hypothesized that there is a single molecular mechanism of primary pro-atherogenic injuries of vessel walls in atherosclerosis and diabetes, which enhances the formation of carbonyl-modified low-density lipoproteins, accumulating in the foam cells. The results of recent studies indicate that oxidatively modified LDL involved not only the primary injury to the vessel walls, but also provoked the development of endothelial dysfunction, so that once again raises the issue of the need for the use of antioxidants to prevent injuries in vascular walls. It can be assumed that the result of years of intensive research of free radical process mechanisms in atherosclerosis and diabetes will be the development of new drugs for the combined therapy of these diseases that can be disposed not only reactive oxygen species and organic free radicals and reactive carbonyls, which are clearly playing an important role in the development of pro-atherogenic injuries.