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Atherosclerosis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 21872

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Guest Editor
Department of Clinical Medicine and Surgery, Federico II University of Naples Medical School, 80131 Naples, Italy
Interests: blood pressure; cardiovascular disease; metabolic syndrome; hypertension; atherosclerosis; cardiovascular epidemiology; metabolism; metabolic diseases; abdominal obesity; internal medicine
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Special Issue Information

Dear Colleagues,

Atherosclerosis is a common condition of vascular aging. However, several factors could influence this process, resulting in increased cardiovascular risk at a young age.

In addition to well-known factors (e.g., high blood pressure, dyslipidemia, diabetes, excess body weight), there are several emerging factors associated with atherosclerosis such as inflammation, endothelial dysfunction, intestinal microbiota alteration, uric acid, vitamin D, or miRNA expression that could potentially explain the residual cardiovascular risk.

This Special Issue on atherosclerosis aims to report the most current scientific evidence available on this topic and reviews of the current literature on the role of emerging factors in the development of atherosclerosis as demonstrated by both experimental and clinical studies, in order to gather a large body of data from which to start to highlight new potential objectives for the reduction in cardiovascular risk.

Dr. Antonio Barbato
Guest Editor

Manuscript Submission Information

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Keywords

  • atherosclerosis
  • cardiovascular risk
  • arterial stiffness
  • blood Pressure
  • vitamin D
  • miRNA
  • inflammation

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Published Papers (7 papers)

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Research

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22 pages, 1225 KiB  
Article
Candidate SNP Markers Significantly Altering the Affinity of TATA-Binding Protein for the Promoters of Human Hub Genes for Atherogenesis, Atherosclerosis and Atheroprotection
by Anton Bogomolov, Sergey Filonov, Irina Chadaeva, Dmitry Rasskazov, Bato Khandaev, Karina Zolotareva, Anna Kazachek, Dmitry Oshchepkov, Vladimir A. Ivanisenko, Pavel Demenkov, Nikolay Podkolodnyy, Ekaterina Kondratyuk, Petr Ponomarenko, Olga Podkolodnaya, Zakhar Mustafin, Ludmila Savinkova, Nikolay Kolchanov, Natalya Tverdokhleb and Mikhail Ponomarenko
Int. J. Mol. Sci. 2023, 24(10), 9010; https://doi.org/10.3390/ijms24109010 - 19 May 2023
Cited by 1 | Viewed by 1583
Abstract
Atherosclerosis is a systemic disease in which focal lesions in arteries promote the build-up of lipoproteins and cholesterol they are transporting. The development of atheroma (atherogenesis) narrows blood vessels, reduces the blood supply and leads to cardiovascular diseases. According to the World Health [...] Read more.
Atherosclerosis is a systemic disease in which focal lesions in arteries promote the build-up of lipoproteins and cholesterol they are transporting. The development of atheroma (atherogenesis) narrows blood vessels, reduces the blood supply and leads to cardiovascular diseases. According to the World Health Organization (WHO), cardiovascular diseases are the leading cause of death, which has been especially boosted since the COVID-19 pandemic. There is a variety of contributors to atherosclerosis, including lifestyle factors and genetic predisposition. Antioxidant diets and recreational exercises act as atheroprotectors and can retard atherogenesis. The search for molecular markers of atherogenesis and atheroprotection for predictive, preventive and personalized medicine appears to be the most promising direction for the study of atherosclerosis. In this work, we have analyzed 1068 human genes associated with atherogenesis, atherosclerosis and atheroprotection. The hub genes regulating these processes have been found to be the most ancient. In silico analysis of all 5112 SNPs in their promoters has revealed 330 candidate SNP markers, which statistically significantly change the affinity of the TATA-binding protein (TBP) for these promoters. These molecular markers have made us confident that natural selection acts against underexpression of the hub genes for atherogenesis, atherosclerosis and atheroprotection. At the same time, upregulation of the one for atheroprotection promotes human health. Full article
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26 pages, 30419 KiB  
Article
PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells
by Maria Francesca Greco, Alessandra Stefania Rizzuto, Marta Zarà, Marco Cafora, Chiara Favero, Giulia Solazzo, Ilaria Giusti, Maria Pia Adorni, Francesca Zimetti, Vincenza Dolo, Cristina Banfi, Nicola Ferri, Cesare R. Sirtori, Alberto Corsini, Silvia Stella Barbieri, Anna Pistocchi, Valentina Bollati, Chiara Macchi and Massimiliano Ruscica
Int. J. Mol. Sci. 2022, 23(21), 13065; https://doi.org/10.3390/ijms232113065 - 28 Oct 2022
Cited by 10 | Viewed by 2262
Abstract
Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted [...] Read more.
Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin. Full article
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Review

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18 pages, 2451 KiB  
Review
Markers of Restenosis after Percutaneous Transluminal Balloon Angioplasty in Patients with Critical Limb Ischemia
by Elvira V. Sobolevskaya, Oleg A. Shumkov, Mikhail A. Smagin, Andrey E. Guskov, Alexandra V. Malysheva, Victor V. Atuchin and Vadim V. Nimaev
Int. J. Mol. Sci. 2023, 24(10), 9096; https://doi.org/10.3390/ijms24109096 - 22 May 2023
Cited by 2 | Viewed by 1968
Abstract
Among cardiovascular diseases, chronic obliterating lesions of the arteries of lower extremities, which are one of the important problems of modern healthcare, are distinguished. In most cases, the cause of damage to the arteries of lower extremities is atherosclerosis. The most severe form [...] Read more.
Among cardiovascular diseases, chronic obliterating lesions of the arteries of lower extremities, which are one of the important problems of modern healthcare, are distinguished. In most cases, the cause of damage to the arteries of lower extremities is atherosclerosis. The most severe form is chronic ischemia, characterized by pain at rest and ischemic ulcers, ultimately increasing the risk of limb loss and cardiovascular mortality. Therefore, patients with critical limb ischemia need limb revascularization. Percutaneous transluminal balloon angioplasty is one of the least invasive and safe approaches, with advantages for patients with comorbidities. However, after this procedure, restenosis is still possible. Early detection of changes in the composition of some molecules as markers of restenosis will help screen patients at the risk of restenosis, as well as find ways to apply efforts for further directions of inhibition of this process. The purpose of this review is to provide the most important and up-to-date information on the mechanisms of restenosis development, as well as possible predictors of their occurrence. The information collected in this publication may be useful in predicting outcomes after surgical treatment and will also find new ways for the target implication to the mechanisms of development of restenosis and atherosclerosis. Full article
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57 pages, 2888 KiB  
Review
Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes
by Evgenii Gusev and Alexey Sarapultsev
Int. J. Mol. Sci. 2023, 24(9), 7910; https://doi.org/10.3390/ijms24097910 - 26 Apr 2023
Cited by 23 | Viewed by 6545
Abstract
Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical [...] Read more.
Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis). Full article
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25 pages, 3984 KiB  
Review
Exploring the Role of Serotonin as an Immune Modulatory Component in Cardiovascular Diseases
by Aqeela Imamdin and Emiel P. C. van der Vorst
Int. J. Mol. Sci. 2023, 24(2), 1549; https://doi.org/10.3390/ijms24021549 - 12 Jan 2023
Cited by 4 | Viewed by 3425
Abstract
Serotonin, also known as 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter in the central nervous system (CNS), but also plays a significant role in peripheral tissues. There is a growing body of evidence suggesting that serotonin influences immune cell responses and contributes to the [...] Read more.
Serotonin, also known as 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter in the central nervous system (CNS), but also plays a significant role in peripheral tissues. There is a growing body of evidence suggesting that serotonin influences immune cell responses and contributes to the development of pathological injury in cardiovascular diseases, such as atherosclerosis, as well as other diseases which occur as a result of immune hyperactivity. In particular, high levels of serotonin are able to activate a multitude of 5-HT receptors found on the surface of immune cells, thereby influencing the process of atherosclerotic plaque formation in arteries. In this review, we will discuss the differences between serotonin production in the CNS and the periphery, and will give a brief outline of the function of serotonin in the periphery. In this context, we will particularly focus on the effects of serotonin on immune cells related to atherosclerosis and identify caveats that are important for future research. Full article
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13 pages, 698 KiB  
Review
Hypertriglyceridemia and Atherosclerotic Carotid Artery Stenosis
by Yoichi Miura and Hidenori Suzuki
Int. J. Mol. Sci. 2022, 23(24), 16224; https://doi.org/10.3390/ijms232416224 - 19 Dec 2022
Cited by 5 | Viewed by 2174
Abstract
Both fasting and non-fasting hypertriglyceridemia have emerged as residual risk factors for atherosclerotic disease. However, it is unclear whether hypertriglyceridemia increases the risks of the progression of carotid artery stenosis. Statins are well known to prevent carotid plaque progression and improve carotid plaque [...] Read more.
Both fasting and non-fasting hypertriglyceridemia have emerged as residual risk factors for atherosclerotic disease. However, it is unclear whether hypertriglyceridemia increases the risks of the progression of carotid artery stenosis. Statins are well known to prevent carotid plaque progression and improve carotid plaque instability. In addition, statin therapy is also known to reduce cerebrovascular events in patients with carotid artery stenosis and to improve clinical outcomes in patients undergoing revascularization procedures. On the other hand, there have been no randomized controlled trials showing that the combination of non-statin lipid-lowering drugs with statins has additional beneficial effects over statin monotherapy to prevent cerebrovascular events and stenosis progression in patients with carotid artery stenosis. In this article, the authors demonstrate the mechanisms of atherosclerosis formation associated with hypertriglyceridemia and the potential role of lipid-lowering drugs on carotid artery stenosis. The authors also review the articles reporting the relationships between hypertriglyceridemia and carotid artery stenosis. Full article
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28 pages, 1420 KiB  
Review
The Impact of Cytokines in Coronary Atherosclerotic Plaque: Current Therapeutic Approaches
by Panagiotis Tsioufis, Panagiotis Theofilis, Konstantinos Tsioufis and Dimitris Tousoulis
Int. J. Mol. Sci. 2022, 23(24), 15937; https://doi.org/10.3390/ijms232415937 - 14 Dec 2022
Cited by 18 | Viewed by 2902
Abstract
Coronary atherosclerosis is a chronic pathological process that involves inflammation together with endothelial dysfunction and lipoprotein dysregulation. Experimental studies during the past decades have established the role of inflammatory cytokines in coronary artery disease, namely interleukins (ILs), tumor necrosis factor (TNF)-α, interferon-γ, and [...] Read more.
Coronary atherosclerosis is a chronic pathological process that involves inflammation together with endothelial dysfunction and lipoprotein dysregulation. Experimental studies during the past decades have established the role of inflammatory cytokines in coronary artery disease, namely interleukins (ILs), tumor necrosis factor (TNF)-α, interferon-γ, and chemokines. Moreover, their value as biomarkers in disease development and progression further enhance the validity of this interaction. Recently, cytokine-targeted treatment approaches have emerged as potential tools in the management of atherosclerotic disease. IL-1β, based on the results of the CANTOS trial, remains the most validated option in reducing the residual cardiovascular risk. Along the same line, colchicine was also proven efficacious in preventing major adverse cardiovascular events in large clinical trials of patients with acute and chronic coronary syndrome. Other commercially available agents targeting IL-6 (tocilizumab), TNF-α (etanercept, adalimumab, infliximab), or IL-1 receptor antagonist (anakinra) have mostly been assessed in the setting of other inflammatory diseases and further testing in atherosclerosis is required. In the future, potential targeting of the NLRP3 inflammasome, anti-inflammatory IL-10, or atherogenic chemokines could represent appealing options, provided that patient safety is proven to be of no concern. Full article
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