Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. This review focuses on the different stages of atherosclerosis development, ranging from endothelial dysfunction to plaque rupture. In addition, the post-transcriptional regulation and modulation of atheroma plaque by microRNAs and lncRNAs, the role of microbiota, and the importance of sex as a crucial risk factor in atherosclerosis are covered here in order to provide a global view of the disease.

Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. Hence, the demand for preclinical research into atherosclerotic inflammation is on the horizon. Indeed, the acquisition of an in-depth knowledge of the molecular and cellular mechanisms of inflammation in atherosclerosis should allow us to identify novel therapeutic targets with translational merits. In this review, we aimed to critically discuss and speculate on the recently identified molecular and cellular mechanisms of inflammation in atherosclerosis. Moreover, we delineated various signaling cascades and proinflammatory responses in macrophages and other leukocytes that promote plaque inflammation and atherosclerosis. In the end, we highlighted potential therapeutic targets, the pros and cons of current interventions, as well as anti-inflammatory and atheroprotective mechanisms.

Cells 2021, 10, 226. https://doi.org/10.3390/cells10020226

Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the
formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can
become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last
three decades, chemokines and their receptors earned great attention in the research of atherosclerosis
as they play a key role in development and progression of atherosclerotic lesions. They orchestrate
activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g.,
increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the
development of foam cells, a key feature developing plaques. In addition, chemokines and their
receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte
responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed
new light on their functions in chronic vascular inflammation. This article reviews recent findings on
the role of immunomodulatory chemokines in the development of atherosclerosis and their potential
for targeting.

Int J Prev Med. 2014 Aug; 5(8): 927–946.

Background:
Atherosclerosis is the major cause of morbidities and mortalities worldwide. In this study we aimed to review the mechanism of atherosclerosis and its risk factors, focusing on new findings in atherosclerosis markers and its risk factors. Furthermore, the role of antioxidants and medicinal herbs in atherosclerosis and endothelial damage has been discussed and a list of important medicinal plants effective in the treatment and prevention of hyperlipidemia and atherosclerosis is presented.

Methods:
The recently published papers about atherosclerosis pathogenesis and herbal medicines effective in the treatment and prevention of hyperlipidemia and atherosclerosis were searched.

Results:
Inflammation has a crucial role in pathogenesis of atherosclerosis. The disease is accompanied by excessive fibrosis of the intima, fatty plaques formation, proliferation of smooth muscle cells, and migration of a group of cells such as monocytes, T cells, and platelets which are formed in response to inflammation. The oxidation of low density lipoprotein (LDL) to Ox-LDL indicates the first step of atherosclerosis in cardiovascular diseases. Malondialdehyde factor shows the level of lipoperoxidation and is a sign of increased oxidative pressure and cardiovascular diseases. In special pathological conditions such as severe hypercholesterolemia, peroxynitrite concentration increases and atherosclerosis and vascular damage are intensified. Medicinal plants have shown to be capable of interacting these or other pathogenesis factors to prevent atherosclerosis.

Conclusions:
The pathogenesis factors involved in atherosclerosis have recently been cleared and the discovery of these factors has brought about new hopes for better prevention and treatment of atherosclerosis.

Signal Transduction and Targeted Therapy volume 7, Article number: 131 (2022)

Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors. Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis. Several signaling pathways, that are associated with the inflammatory response, have been implicated within atherosclerosis such as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt signaling pathways, which are of importance for atherosclerosis development and regression. Targeting inflammatory pathways, especially the NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β, could represent an attractive new route for the treatment of atherosclerotic diseases. Herein, we summarize the knowledge on cellular participants and key inflammatory signaling pathways in atherosclerosis, and discuss the preclinical studies targeting these key pathways for atherosclerosis, the clinical trials that are going to target some of these processes, and the effects of quelling inflammation and atherosclerosis in the clinic.

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Abstract
Background
Inflammation links to atherosclerosis and its complications in various experimental investigations. Animal studies have implicated numerous inflammatory mediators in the initiation and complication of atherosclerosis. Numerous studies in humans have shown associations of biomarkers of inflammation with cardiovascular events provoked by atheromata. Inflammatory status, determined by the biomarker C-reactive protein, can guide the allocation of statin therapy to individuals without elevated low-density lipoprotein (LDL) concentrations to prevent first ever adverse cardiovascular events.

Content
Until recently, no direct evidence has shown that an intervention that selectively limits inflammation can improve outcomes in patients with atherosclerosis. A recent study, based on decades of preclinical investigation, treated patients who had sustained a myocardial infarction and whose LDL was well-controlled on statin treatment with an antibody that neutralizes interleukin-1 beta. This trial, conducted in over 10 000 individuals, showed a reduction in major adverse cardiac events, establishing for the first time the clinical efficacy of an anti-inflammatory intervention in atherosclerosis. Two large subsequent studies have shown that colchicine treatment can also prevent recurrent events in patients recovering from an acute coronary syndrome or in the stable phase of coronary artery disease. These clinical trials have transformed inflammation in atherosclerosis from theory to practice.

Summary
Much work remains to optimize further anti-inflammatory interventions, minimize unwanted actions, and refine patient selection. This long road from discovery in the laboratory to successful clinical trials represents a victory for medical science, and opens a new avenue to reducing the risk that remains despite current treatments for atherosclerosis.

Clinica Chimica Acta Volume 424, 23 September 2013, Pages 245–252

Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage foam cell formation will help to develop novel therapeutic interventions for atherosclerosis.

BMB Rep. 2011 Aug;44(8):497-505.

Abstract

Reactive oxygen species (ROS), which include superoxide anions and peroxides, induce oxidative stress, contributing to the initiation and progression of cardiovascular diseases involving atherosclerosis. The endogenous and exogenous factors hypercholesterolemia, hyperglycemia, hypertension, and shear stress induce various enzyme systems such as nicotinamide adenine dinucleotide (phosphate) oxidase, xanthine oxidase, and lipoxygenase in vascular and immune cells, which generate ROS. Besides inducing oxidative stress, ROS mediate signaling pathways involved in monocyte adhesion and infiltration, platelet activation, and smooth muscle cell migration. A number of antioxidant enzymes (e.g., superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins) regulate ROS in vascular and immune cells. Atherosclerosis results from a local imbalance between ROS production and these antioxidant enzymes. In this review, we will discuss 1) oxidative stress and atherosclerosis, 2) ROS-dependent atherogenic signaling in endothelial cells, macrophages, and vascular smooth muscle cells, 3) roles of peroxidases in atherosclerosis, and 4) antioxidant drugs and therapeutic perspectives.

https://www.jstage.jst.go.jp/article/jat/17/1/17_2600/_pdf/-char/en

In recent years, several studies have used the measurement of carotid intima-media thickness (IMT) as a marker of early atherosclerosis: IMT has been shown to correlate significantly with the presence of coronary artery disease (CAD) and to predict fatal and not fatal cerebro- and cardio-vascular events. These findings highlight the importance of recognizing and managing early stages of atherosclerosis for effective cardiovascular prevention. Beyond traditional established cardiovascular risk factors, inflammation has been shown to be crucial throughout atherosclerosis from endothelial dysfunction to plaque rupture and thrombosis. Several studies have shown the existence of a strong relation between CAD and fibrinogen or highly sensitive C-reactive protein (hs-CRP) levels and their predictive role has been examined through stratification or multivariable statistical analyses: levels of these markers of inflammation have been independently associated with the incidence of coronary events after adjusting for traditional cardiovascular risk factors. Recent studies have further addressed the importance of therapeutical modulation of hs-CRP levels in high-risk patients for the prevention of vascular events. The strong relationship between hs-CRP and IMT may potentially account for the complex role of hs-CRP and IMT in the pathogenesis of cardiovascular events. However, beyond the utility of measuring markers of inflammation to assess patients with subclinical carotid atherosclerosis at higher risk of vascular events, further studies are needed to evaluate the therapeutic implications in this category of patients.

Angiology Volume 58, Number 5, 2007

Atherosclerosis is the root cause of the biggest killer of the 21st century. Mechanisms contributing to atherogenesis are multiple and complex. A number of theories—including the role of dyslipidemia, hypercoagulability, oxidative stress, endothelial dysfunction, and inflammation and infection by certain pathogens—have been propounded from time to time explain this complex phenomenon. Recently it has been suggested that atherosclerosis is a multifactorial, multistep disease that involves chronic inflammation at every step, from initiation to progression, and that all the risk factors contribute to pathogenesis by aggravating the underlying inflammatory process. A better understanding of the pathogenesis of atherosclerosis will aid in devising pharmaceutical and lifestyle modifications for reducing mortality resulting from coronary artery disease (CAD).

Dr. Yalçın Başaran
Prof. Dr. Yavuz Baykal sunumu

Mayo Clinic Proceedings February 2005 vol. 80 no. 2 219-230

Although most patients who experience a coronary heart disease (CHD) event have one or more of the conventional risk factors for atherosclerosis, so do many people who have not yet experienced such an event. Therefore, predictive models based on conventional risk factors have a lower than desired accuracy, providing a stimulus to search for new tools to refine CHD risk prediction. In particular, there is intense interest in evaluating circulating biomarkers related to the atherosclerotic process that might add to our ability to better predict CHD risk. One such group of biomarkers was termed conditional risk factors in an American Heart Association/American College of Cardiology statement in 1999. The conditional risk factors include homocysteine, fibrinogen, lipoprotein(a), low-density lipoprotein particle size, and Creactive protein. This review updates the conditional risk factors. The main focus is on the potential utility of these risk factors, which are currently available to clinicians, in the prediction of CHD risk in asymptomatic persons. The putative mechanisms of risk, available assays, evidence for association with CHD, and the clinical implications thereof are discussed for each of the risk factors.