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Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (10 October 2023) | Viewed by 14467

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Dr. Evgeny E. Bezsonov

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Guest Editor

1. Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
2. Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Center of Surgery”, 117418 Moscow, Russia
3. Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 105043 Moscow, Russia
Interests: atherosclerosis; mitophagy; atherogenicity; atherosclerosis; autoantibodies; inflammation; innate immunity; amyloid
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Prof. Dr. Igor A. Sobenin

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Guest Editor

Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, Moscow, Russia
Interests: atherosclerosis; atherogenesis; cellular and molecular mechanisms; pathogenetic prevention; pathogenetic treatment
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Prof. Dr. Alexander N. Orekhov

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Guest Editor

1. Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
2. Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia
Interests: atherosclerosis; mitophagy; atherogenicity; autoantibodies; inflammation; innate immunity; cell test; macrophage; membrane transport; modified low density lipoprotein; monocyte; transcriptome; trans-sialydase; enzymatic test; cytokine; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue "Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology" and Special Issue "Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0".

Lipid-lowering therapy (primarily statins) was revolutionary at one time by opening up the possibility of therapeutic regression of atherosclerosis. However, atherosclerosis and related diseases are multifactorial, which requires a search for new nonlipid therapeutic targets. Anti-inflammatory therapy with a monoclonal antibody that targets IL-1b (the CANTOS study) possesses significant cardiovascular benefits without affecting lipid levels. These findings have forced us to seriously turn towards anti-inflammatory therapy at the immune level. The ideas of Rokitansky and Virchow (19th century) about atherosclerosis as an inflammatory process again became popular along with Anichkov's cholesterol theory (early 20th century). Current knowledge links lipid-induced activation of the innate and adaptive immunity in the chronic inflammation that explains many mechanisms of atherogenesis, including the role of immune cells, such as macrophages, dendritic cells, and a variety of effector molecules, including cytokines. This Special Issue is focused on the current progress in genetic studies, drug discovery, and drug application in atherosclerotic diseases. In recent years, great advances in genetic studies and the accumulating pool of available data have made possible the discovery of molecular mechanisms of a number of chronic human pathologies, investigation of genetic predispositions to various disorders, and identification of numerous potential therapeutic targets. This progress in turn has been followed by a number of preclinical and clinical trials that collect important data on the safety and efficacy of new drugs. Research articles provide numerous examples of successful development and the application of drugs and gene therapies of cardiovascular diseases, cancer, and other human pathologies. Moreover, a significant amount of data is coming from clinical applications and molecular studies of traditional medicines.

Dr. Evgeny E. Bezsonov
Prof. Dr. Igor A. Sobenin
Prof. Dr. Alexander N. Orekhov
Guest Editors

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Keywords

arterial hypertension
atherogenesis
atherogenic antigens
atherosclerosis
coronary heart disease
dendritic cells
diabetes mellitus
genetic markers
innate and adaptive immune systems
lipoprotein metabolism
metabolic syndrome
mitochondrion
neurodegenerative diseases
stroke

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Published Papers (6 papers)

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Research

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28 pages, 783 KiB

Open AccessArticle

Immunological Profile and Markers of Endothelial Dysfunction in Elderly Patients with Cognitive Impairments

by Nikolay V. Goncharov, Polina I. Popova, Igor V. Kudryavtsev, Alexey S. Golovkin, Irina V. Savitskaya, Piotr P. Avdonin, Ekaterina A. Korf, Natalia G. Voitenko, Daria A. Belinskaia, Maria K. Serebryakova, Natalia V. Matveeva, Natalia O. Gerlakh, Natalia E. Anikievich, Marina A. Gubatenko, Irina A. Dobrylko, Andrey S. Trulioff, Arthur D. Aquino, Richard O. Jenkins and Pavel V. Avdonin

Int. J. Mol. Sci. 2024, 25(3), 1888; https://doi.org/10.3390/ijms25031888 - 4 Feb 2024

Cited by 2 | Viewed by 2275

Abstract

The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. Further, damage to the endothelium can be both a cause and a consequence of many diseases, especially in elderly people. The purpose of this study was to carry out immunological and biochemical profiling of elderly people with acute ischemic stroke (AIS), chronic cerebral circulation insufficiency (CCCI), prediabetes or newly diagnosed type II diabetes mellitus (DM), and subcortical ischemic vascular dementia (SIVD). Socio-demographic, lifestyle, and cognitive data were obtained. Biochemical, hematological, and immunological analyses were carried out, and extracellular vesicles (EVs) with endothelial CD markers were assessed. The greatest number of significant deviations from conditionally healthy donors (HDs) of the same age were registered in the SIVD group, a total of 20, of which 12 were specific and six were non-specific but with maximal differences (as compared to the other three groups) from the HDs group. The non-specific deviations were for the MOCA (Montreal Cognitive Impairment Scale), the MMSE (Mini Mental State Examination) and life satisfaction self-assessment scores, a decrease of albumin levels, and ADAMTS13 (a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13) activity, and an increase of the VWF (von Willebrand factor) level. Considering the significant changes in immunological parameters (mostly Th17-like cells) and endothelial CD markers (CD144 and CD34), vascular repair was impaired to the greatest extent in the DM group. The AIS patients showed 12 significant deviations from the HD controls, including three specific to this group. These were high NEFAs (non-esterified fatty acids) and CD31 and CD147 markers of EVs. The lowest number of deviations were registered in the CCCI group, nine in total. There were significant changes from the HD controls with no specifics to this group, and just one non-specific with a maximal difference from the control parameters, which was α1-AGP (alpha 1 acid glycoprotein, orosomucoid). Besides the DM patients, impairments of vascular repair were also registered in the CCCI and AIS patients, with a complete absence of such in patients with dementia (SIVD group). On the other hand, microvascular damage seemed to be maximal in the latter group, considering the biochemical indicators VWF and ADAMTS13. In the DM patients, a maximum immune response was registered, mainly with Th17-like cells. In the CCCI group, the reaction was not as pronounced compared to other groups of patients, which may indicate the initial stages and/or compensatory nature of organic changes (remodeling). At the same time, immunological and biochemical deviations in SIVD patients indicated a persistent remodeling in microvessels, chronic inflammation, and a significant decrease in the anabolic function of the liver and other tissues. The data obtained support two interrelated assumptions. Taking into account the primary biochemical factors that trigger the pathological processes associated with vascular pathology and related diseases, the first assumption is that purine degradation in skeletal muscle may be a major factor in the production of uric acid, followed by its production by non-muscle cells, the main of which are endothelial cells. Another assumption is that therapeutic factors that increase the levels of endothelial progenitor cells may have a therapeutic effect in reducing the risk of cerebrovascular disease and related neurodegenerative diseases. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0)

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17 pages, 4936 KiB

Open AccessArticle

Dual-Specificity Phosphatase 6 Deficiency Attenuates Arterial-Injury-Induced Intimal Hyperplasia in Mice

by Candra D. Hamdin, Meng-Ling Wu, Chen-Mei Chen, Yen-Chun Ho, Wei-Cheng Jiang, Pei-Yu Gung, Hua-Hui Ho, Huai-Chia Chuang, Tse-Hua Tan and Shaw-Fang Yet

Int. J. Mol. Sci. 2023, 24(24), 17136; https://doi.org/10.3390/ijms242417136 - 5 Dec 2023

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Abstract

In response to injury, vascular smooth muscle cells (VSMCs) of the arterial wall dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The ERK1/2 pathway participates in cellular proliferation and migration, while dual-specificity phosphatase 6 (DUSP6, also named MKP3) can dephosphorylate activated ERK1/2. We showed that DUSP6 was expressed in low baseline levels in normal arteries; however, arterial injury significantly increased DUSP6 levels in the vessel wall. Compared with wild-type mice, Dusp6-deficient mice had smaller neointima. In vitro, IL-1β induced DUSP6 expression and increased VSMC proliferation and migration. Lack of DUSP6 reduced IL-1β-induced VSMC proliferation and migration. DUSP6 deficiency did not affect IL-1β-stimulated ERK1/2 activation. Instead, ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1β, indicating that ERK1/2 functions upstream of DUSP6 to regulate DUSP6 expression in VSMCs rather than downstream as a DUSP6 substrate. IL-1β decreased the levels of cell cycle inhibitor p27 and cell–cell adhesion molecule N-cadherin in VSMCs, whereas lack of DUSP6 maintained their high levels, revealing novel functions of DUSP6 in regulating these two molecules. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining p27 and N-cadherin levels. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0)

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7 pages, 777 KiB

Open AccessCommunication

miR-33a and Its Association with Lipid Profile in Patients with Carotid Atherosclerosis

by Marine M. Tanashyan, Alla A. Shabalina, Polina I. Kuznetsova and Anton A. Raskurazhev

Int. J. Mol. Sci. 2023, 24(7), 6376; https://doi.org/10.3390/ijms24076376 - 28 Mar 2023

Cited by 1 | Viewed by 1513

Abstract

Atherosclerosis is a chronic inflammatory disease with a complex, multifactorial pathogenesis, which includes lipid metabolism alterations. miR-33a is a microRNA that plays a key role in cholesterol efflux and promotes atherosclerosis, yet its relationship with lipid markers in carotid atherosclerosis (CA) remains unclear. The objective is to evaluate possible associations between miR-33a expression and lipid biomarkers in patients with CA. This was a prospective study that included 61 patients (median age 66.0 years, 55.7% male) with evidence of CA. Lipid profile (total cholesterol, triglycerides [TG], high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol) was analyzed. Extraction and quantification of miR-33a-5p/3p was performed according to protocol. Patients were further divided depending on the target LDL level (<1.8 mmol/L). Patients with CA had relatively favorable LDL levels with a median of 2.0 mmol/L. Both miR-33a-5p and miR-33a-3p levels were lower in patients with less than targeted LDL levels (37.4 and 38.3 vs. 41.8 and 42.5 respectively, p < 0.05). A significant positive correlation between expression levels of miR-33a-5p/3p and degree of carotid stenosis was found (r = 0.44 and r = 0.38 respectively, p < 0.05). In a univariate linear regression model miR-33a-3p/5p was positively associated with LDL cholesterol (p = 0.02). miR-33a up-regulation is associated with CA and may, in fact, be a key player by targeting cholesterol metabolism. A decrease in LDL cholesterol (<1.8 mmol/L) corresponded to lower levels of miR-33a, yet the direction and causality of this association remains unclear. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0)

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7 pages, 250 KiB

Open AccessArticle

DUOX1 Gene Missense Mutation Confers Susceptibility on Type 2 Amiodarone-Induced Thyrotoxicosis

by Olga Biakina, Yulia Mitina, Daria Gognieva, Marina Axenova, Alexandra Ermolaeva, Afina Bestavashvili, Valentin Fadeev, Abram Syrkin and Philipp Kopylov

Int. J. Mol. Sci. 2023, 24(4), 4016; https://doi.org/10.3390/ijms24044016 - 16 Feb 2023

Cited by 1 | Viewed by 1708

Abstract

Possible triggers and genetic markers involved in pathogenesis of amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) are currently unknown. This study aimed to analyze the association between polymorphisms in the genes involved in thyroid hormones biosynthesis and metabolism. Thirty-nine consecutive patients with confirmed type 2 amiodarone-induced thyrotoxicosis were enrolled; 39 patients on the same therapy for at least 6 months without thyroid pathology were included as a control group. A comparative study was carried out to determine the distribution and genotypes of polymorphic markers of the (Na)-iodide symporter (NIS) genes (rs7250346, C/G substitution), thyroid stimulating hormone receptor (TSHR) (rs1991517, C/G substitution), thyroid peroxidase (TPO) (rs 732609, A/C substitution), DUOX 1-1 (C/T substitution), DUOX 1-2 (G/T substitution), DUOX 1-3 (C/T substitution), glutathione peroxidase 3 (GPX3) (C/T substitution), glutathione peroxidase 4 (GPX4) (C/T substitution). Statistical analysis was performed using Prism (Version 9.0.0 (86)). This study showed that the risk of AIT2 is 3.18 times higher in the G/T of the DUOX1 gene carriers. This study is the first report of genetic markers associated with amiodarone-related adverse events conducted in humans. The obtained results indicate the necessity for a personalized approach to amiodarone administration. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0)

13 pages, 3914 KiB

Open AccessArticle

Microarray Expression Profile of Myricetin-Treated THP-1 Macrophages Exhibits Alterations in Atherosclerosis-Related Regulator Molecules and LXR/RXR Pathway

by Etimad Huwait, Rehab Almassabi, Sanaa Almowallad, Salma Saddeek, Sajjad Karim, Gauthaman Kalamegam and Zeenat Mirza

Int. J. Mol. Sci. 2023, 24(1), 278; https://doi.org/10.3390/ijms24010278 - 23 Dec 2022

Cited by 2 | Viewed by 2604

Abstract

Atherosclerosis is a chronic inflammation characterized by macrophage infiltration, lipid deposition, and arterial wall thickening. Prevention of atherosclerosis by nutraceuticals is gaining attention. Myricetin, a dietary flavonol, is claimed to possess anti-atherosclerosis properties. We studied myricetin’s effect on the atherosclerosis-associated molecular mechanism. Cytotoxicity and proliferation testing to check the viability of myricetin-treated THP-1 macrophages and monocyte migration study in the presence and absence of myricetin was performed. The whole transcriptome analysis was conducted using the Affymetrix microarray platform. The Partek genomics suite for detecting differentially expressed genes (DEGs) and ingenuity pathway analysis was used to identify canonical pathways. Cytotoxicity assays exhibited no significant toxicity in THP-1 macrophages treated with different myricetin concentrations (10–200 μM). Genome-wide expression profiling revealed 58 DEGs (53 upregulated and 5 downregulated) in myricetin-treated THP-1 macrophages. Pathway analysis revealed inhibition of LXR/RXR activation and angiogenesis inhibition by thrombospondin-1 and activated phagocytosis in myricetin-treated THP-1 macrophages. The cytotoxicity assay shows myricetin as a safe phytochemical. In vitro and in silico pathway studies on THP-1 macrophages showed that they can inhibit THP-1 monocyte migration and alter the cholesterol efflux mediated via LXR/RXR signaling. Therefore, myricetin could help in the prevention of cell infiltration in atherosclerotic plaque with reduced risk of stroke or brain damage. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0)

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25 pages, 2133 KiB

Open AccessReview

The IL-1 Family and Its Role in Atherosclerosis

by Leticia González, Katherine Rivera, Marcelo E. Andia and Gonzalo Martínez Rodriguez

Int. J. Mol. Sci. 2023, 24(1), 17; https://doi.org/10.3390/ijms24010017 - 20 Dec 2022

Cited by 26 | Viewed by 4057

Abstract

The IL-1 superfamily of cytokines is a central regulator of immunity and inflammation. The family is composed of 11 cytokines (with agonist, antagonist, and anti-inflammatory properties) and 10 receptors, all tightly regulated through decoy receptor, receptor antagonists, and signaling inhibitors. Inflammation not only is an important physiological response against infection and injury but also plays a central role in atherosclerosis development. Several clinical association studies along with experimental studies have implicated the IL-1 superfamily of cytokines and its receptors in the pathogenesis of cardiovascular disease. Here, we summarize the key features of the IL-1 family, its role in immunity and disease, and how it helps shape the development of atherosclerosis. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 3.0)

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