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Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0

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 (20 August 2022) | Viewed by 52540

Special Issue Editors

Dr. Evgeny E. Bezsonov

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Igor A. Sobenin

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Alexander N. Orekhov

E-Mail Website
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" (https://www.mdpi.com/journal/ijms/special_issues/immunopathology_atherosclerosis).

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. Igor A. Sobenin
Prof. Dr. Alexander N. Orekhov
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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

Published Papers (17 papers)

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Research

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11 pages, 2034 KiB  
Article
MicroRNA and Hemostasis Profile of Carotid Atherosclerosis
by Anton A. Raskurazhev, Polina I. Kuznetsova, Alla A. Shabalina and Marine M. Tanashyan
Int. J. Mol. Sci. 2022, 23(18), 10974; https://doi.org/10.3390/ijms231810974 - 19 Sep 2022
Cited by 5 | Viewed by 1834
Abstract
Carotid atherosclerosis (CA) is an important risk factor for ischemic stroke. We described the miRNA and hemostasis profile of patients with moderate and advanced stages of carotid atherosclerosis and elucidated potential correlations with hemostatic activation. A prospective case-control study included 61 patients with [...] Read more.
Carotid atherosclerosis (CA) is an important risk factor for ischemic stroke. We described the miRNA and hemostasis profile of patients with moderate and advanced stages of carotid atherosclerosis and elucidated potential correlations with hemostatic activation. A prospective case-control study included 61 patients with evidence of carotid atherosclerosis (via ultrasound). The study population was divided into groups depending on the degree of carotid artery stenosis: 60% or more (advanced) and <60% (moderate). All patients underwent the following blood tests: general blood test, hemostatic parameters and microRNA. Extraction of microRNA was performed using Leukocyte RNA Purification Kit (NORGEN Biotec Corp., Thorold, ON, Canada); miRNA quantification was performed via RT-PCR. Statistical analysis was performed in R programming language (v. 4.1.0) using RSudio. MicroRNA expression profile was different depending on CA degree. MiR-33a-5p/3p levels were higher in patients with ≥60% carotid stenosis (42.70 and 42.45 versus 38.50 and 38.50, respectively, p < 0.05). Almost complete separation can be visualized with the levels of miR-126-5p: 9.50 in the moderate CA group versus 5.25 in the advanced CA (p < 0.001). MiR-29-5p was higher in the moderate CA group: 28.60 [25.50;33.05] than in advanced CA group: 25.75 [24.38;29.50] (p = 0.086); miR-29-3p was also higher in the moderate CA group: 10.36 [8.60;14.99] than in advanced CA group: 8.46 [7.47;10.3] (p = 0.001). By-group pairwise correlation analyses revealed at least three clusters with significant positive correlations in the moderate CA group: miR-29-3p with factors V and XII (r = 0.53 and r = 0.37, respectively, p < 0.05); miR-21-5p with ADAMTS13, erythrocyte sedimentation rate and D-dimer (r = 0.42, r = 0.36 and r = 0.44, respectively, p < 0.05); stenosis degree with miR-33a-5p/3p and factor VIII levels (r = 0.43 (both) and r = 0.62, respectively, p < 0.05). Hemostasis parameters did not reveal significant changes in CA patients: the only statistically significant differences concerned factor VIII, plasminogen and (marginally significant) ADAMTS-13 and protein C. Down-regulation of miR-126-5p expression has been identified as a promising biomarker of advanced carotid atherosclerosis with high specificity and sensitivity. Correlation cluster analysis showed potential interplay between miRNAs and hemostatic activation in the setting of carotid atherosclerosis. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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15 pages, 5005 KiB  
Article
Deletion of Macrophage-Specific Glycogen Synthase Kinase (GSK)-3α Promotes Atherosclerotic Regression in Ldlr−/− Mice
by Sarvatit Patel, Lauren Mastrogiacomo, Madison Fulmer, Yuanyuan Shi and Geoff H. Werstuck
Int. J. Mol. Sci. 2022, 23(16), 9293; https://doi.org/10.3390/ijms23169293 - 18 Aug 2022
Viewed by 1582
Abstract
Recent evidence from our laboratory suggests that impeding ER stress–GSK3α/β signaling attenuates the progression and development of atherosclerosis in mouse model systems. The objective of this study was to determine if the tissue-specific genetic ablation of GSK3α/β could promote the regression of established [...] Read more.
Recent evidence from our laboratory suggests that impeding ER stress–GSK3α/β signaling attenuates the progression and development of atherosclerosis in mouse model systems. The objective of this study was to determine if the tissue-specific genetic ablation of GSK3α/β could promote the regression of established atherosclerotic plaques. Five-week-old low-density lipoprotein receptor knockout (Ldlr−/−) mice were fed a high-fat diet for 16 weeks to promote atherosclerotic lesion formation. Mice were then injected with tamoxifen to induce macrophage-specific GSK3α/β deletion, and switched to standard diet for 12 weeks. All mice were sacrificed at 33 weeks of age and atherosclerosis was quantified and characterized. Female mice with induced macrophage-specific GSK3α deficiency, but not GSK3β deficiency, had reduced plaque volume (~25%) and necrosis (~40%) in the aortic sinus, compared to baseline mice. Atherosclerosis was also significantly reduced (~60%) in the descending aorta. Macrophage-specific GSK3α-deficient mice showed indications of increased plaque stability and reduced inflammation in plaques, as well as increased CCR7 and ABCA1 expression in lesional macrophages, consistent with regressive plaques. These results suggest that GSK3α ablation promotes atherosclerotic plaque regression and identify GSK3α as a potential target for the development of new therapies to treat existing atherosclerotic lesions in patients with cardiovascular disease. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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14 pages, 3550 KiB  
Article
Local Accumulation of Lymphocytes in the Intima of Human Aorta Is Associated with Giant Multinucleated Endothelial Cells: Possible Explanation for Mosaicism of Atherosclerosis
by Nikita G. Nikiforov, Dmitry V. Zlenko, Varvara A. Orekhova, Alexandra A. Melnichenko and Alexander N. Orekhov
Int. J. Mol. Sci. 2022, 23(3), 1059; https://doi.org/10.3390/ijms23031059 - 19 Jan 2022
Cited by 4 | Viewed by 2036
Abstract
Distribution of different types of atherosclerotic lesions in the arterial wall is not diffuse, but is characterized by mosaicism. The causes of such distribution remain to be established. At the early stages of atherogenesis, low-density lipoprotein (LDL) particles and immune cells penetrate into [...] Read more.
Distribution of different types of atherosclerotic lesions in the arterial wall is not diffuse, but is characterized by mosaicism. The causes of such distribution remain to be established. At the early stages of atherogenesis, low-density lipoprotein (LDL) particles and immune cells penetrate into the intimal layer of the arterial wall through the endothelium. In adult humans, the luminal surface of the arterial wall is a heterogeneous monolayer of cells with varying morphology including typical endothelial cells (ECs) and multinucleated variant endothelial cells (MVECs). We hypothesized that distribution of MVECs in the endothelial monolayer can be related to the distribution pattern of early atherosclerotic lesions. We obtained en face preparations of intact adult (22–59 years old) aortic wall sections that allowed us to study the endothelial monolayer and the subendothelial layer. We compared the distribution of MVECs in the endothelial monolayer with the localization of early atherosclerotic lesions in the subendothelial layer, which were characterized by lipid accumulation and immune cell recruitment. In primary culture, MVECs demonstrated increased phagocytic activity compared to mononuclear ECs. Moreover, we have shown that unaffected aortic intima contained associates formed as a result of aggregation and/or fusion of LDL particles that are non-randomly distributed. This indicated that MVECs may be involved in the accumulation of LDL in the subendothelial layer through increased transcytosis. Interaction of LDL with subendothelial cells of human aorta in primary culture increased their adhesive properties toward circulating immune cells. Study of unaffected aortic intima revealed non-random distribution of leukocytes in the subendothelial layer and increased localization of CD45+ leukocytes in the subendothelial layer adjacent to MVECs. Together, our observations indicate that MVECs may be responsible for the distribution of atherosclerotic lesions in the arterial wall by participating in LDL internalization and immune cell recruitment. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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12 pages, 1522 KiB  
Article
Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout Mice
by Yoshinori Ohmura, Naoki Ishimori, Akimichi Saito, Takashi Yokota, Shunpei Horii, Satoshi Tokuhara, Kazuya Iwabuchi and Hiroyuki Tsutsui
Int. J. Mol. Sci. 2021, 22(22), 12451; https://doi.org/10.3390/ijms222212451 - 18 Nov 2021
Cited by 2 | Viewed by 1783
Abstract
The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens, play a crucial [...] Read more.
The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens, play a crucial role in atherogenesis. However, it remained unclear whether iNKT cells are also involved in plaque instability. Apolipoprotein E (apoE) knockout mice were fed a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. Moreover, the SD- and the HFD-fed mice were divided into two groups according to the intraperitoneal injection of α-galactosylceramide (αGC) that specifically activates iNKT cells or phosphate-buffered saline alone (PBS). ApoE/Jα18 double knockout mice, which lack iNKT cells, were also fed an SD or HFD. Plaque instability was assessed at the brachiocephalic artery by the histological analysis. In the HFD group, αGC significantly enhanced iNKT cell infiltration and exacerbated atherosclerotic plaque instability, whereas the depletion of iNKT cells attenuated plaque instability compared to PBS-treated mice. Real-time PCR analyses in the aortic tissues showed that αGC administration significantly increased expressional levels of inflammatory genes such as IFN-γ and MMP-2, while the depletion of iNKT cells attenuated these expression levels compared to those in the PBS-treated mice. Our findings suggested that iNKT cells are involved in the exacerbation of plaque instability via the activation of inflammatory cells and upregulation of MMP-2 in the vascular tissues. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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12 pages, 2093 KiB  
Article
The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype
by Anna Kiepura, Kamila Stachyra, Anna Wiśniewska, Katarzyna Kuś, Klaudia Czepiel, Maciej Suski, Magdalena Ulatowska-Białas, Marcin Surmiak and Rafał Olszanecki
Int. J. Mol. Sci. 2021, 22(18), 9772; https://doi.org/10.3390/ijms22189772 - 09 Sep 2021
Cited by 8 | Viewed by 2536
Abstract
Background: Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic [...] Read more.
Background: Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic inflammatory diseases, including atherosclerosis, obesity and NAFLD, through to its anti-inflammatory effect. Methods: The present study investigates the influence of prolonged treatment with TUG-891-FFAR4 agonist on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods. Results: TUG-891 administration has led to the reduction of atherosclerotic plaque size and necrotic cores in an apoE-knockout mice model. TUG-891-treated mice were administered subcutaneously at a dose of 20 mg/kg three times a week for 4 months. The FFAR4 agonist reduced the content of pro-inflammatory M1-like macrophages content in atherosclerotic plaques, as evidenced by immunohistochemical phenotyping and molecular methods. In atherosclerotic plaque, the population of smooth muscle cells increased as evidenced by α-SMA staining. We observed changes in G-CSF and eotaxin markers in the plasma of mice; changes in the levels of these markers in the blood may be related to macrophage differentiation. Importantly, we observed a significant increase in M2-like macrophage cells in atherosclerotic plaque and peritoneum. Conclusions: Prolonged administration of TUG-891 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR4 receptor holds promise for a new approach in the prevention or treatment of atherosclerosis. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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Review

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11 pages, 558 KiB  
Review
Targeting Epigenetic Regulation of Cardiomyocytes through Development for Therapeutic Cardiac Regeneration after Heart Failure
by Lindsay Kraus
Int. J. Mol. Sci. 2022, 23(19), 11878; https://doi.org/10.3390/ijms231911878 - 06 Oct 2022
Cited by 6 | Viewed by 1823
Abstract
Cardiovascular diseases are the leading cause of death globally, with no cure currently. Therefore, there is a dire need to further understand the mechanisms that arise during heart failure. Notoriously, the adult mammalian heart has a very limited ability to regenerate its functional [...] Read more.
Cardiovascular diseases are the leading cause of death globally, with no cure currently. Therefore, there is a dire need to further understand the mechanisms that arise during heart failure. Notoriously, the adult mammalian heart has a very limited ability to regenerate its functional cardiac cells, cardiomyocytes, after injury. However, the neonatal mammalian heart has a window of regeneration that allows for the repair and renewal of cardiomyocytes after injury. This specific timeline has been of interest in the field of cardiovascular and regenerative biology as a potential target for adult cardiomyocyte repair. Recently, many of the neonatal cardiomyocyte regeneration mechanisms have been associated with epigenetic regulation within the heart. This review summarizes the current and most promising epigenetic mechanisms in neonatal cardiomyocyte regeneration, with a specific emphasis on the potential for targeting these mechanisms in adult cardiac models for repair after injury. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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15 pages, 649 KiB  
Review
From Diabetes to Atherosclerosis: Potential of Metformin for Management of Cardiovascular Disease
by Anastasia V. Poznyak, Larisa Litvinova, Paolo Poggio, Donato Moschetta, Vasily Nikolaevich Sukhorukov and Alexander N. Orekhov
Int. J. Mol. Sci. 2022, 23(17), 9738; https://doi.org/10.3390/ijms23179738 - 27 Aug 2022
Cited by 9 | Viewed by 2589
Abstract
Atherosclerosis is a common cause of cardiovascular disease, which, in turn, is often fatal. Today, we know a lot about the pathogenesis of atherosclerosis. However, the main knowledge is that the disease is extremely complicated. The development of atherosclerosis is associated with more [...] Read more.
Atherosclerosis is a common cause of cardiovascular disease, which, in turn, is often fatal. Today, we know a lot about the pathogenesis of atherosclerosis. However, the main knowledge is that the disease is extremely complicated. The development of atherosclerosis is associated with more than one molecular mechanism, each making a significant contribution. These mechanisms include endothelial dysfunction, inflammation, mitochondrial dysfunction, oxidative stress, and lipid metabolism disorders. This complexity inevitably leads to difficulties in treatment and prevention. One of the possible therapeutic options for atherosclerosis and its consequences may be metformin, which has already proven itself in the treatment of diabetes. Both diabetes and atherosclerosis are complex metabolic diseases, the pathogenesis of which involves many different mechanisms, including those common to both diseases. This makes metformin a suitable candidate for investigating its efficacy in cardiovascular disease. In this review, we highlight aspects such as the mechanisms of action and targets of metformin, in addition to summarizing the available data from clinical trials on the effective reduction of cardiovascular risks. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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18 pages, 822 KiB  
Review
Role of the mtDNA Mutations and Mitophagy in Inflammaging
by Siarhei A. Dabravolski, Nikita G. Nikiforov, Alexander D. Zhuravlev, Nikolay A. Orekhov, Andrey V. Grechko and Alexander N. Orekhov
Int. J. Mol. Sci. 2022, 23(3), 1323; https://doi.org/10.3390/ijms23031323 - 25 Jan 2022
Cited by 12 | Viewed by 3721
Abstract
Ageing is an unavoidable multi-factorial process, characterised by a gradual decrease in physiological functionality and increasing vulnerability of the organism to environmental factors and pathogens, ending, eventually, in death. One of the most elaborated ageing theories implies a direct connection between ROS-mediated mtDNA [...] Read more.
Ageing is an unavoidable multi-factorial process, characterised by a gradual decrease in physiological functionality and increasing vulnerability of the organism to environmental factors and pathogens, ending, eventually, in death. One of the most elaborated ageing theories implies a direct connection between ROS-mediated mtDNA damage and mutations. In this review, we focus on the role of mitochondrial metabolism, mitochondria generated ROS, mitochondrial dynamics and mitophagy in normal ageing and pathological conditions, such as inflammation. Also, a chronic form of inflammation, which could change the long-term status of the immune system in an age-dependent way, is discussed. Finally, the role of inflammaging in the most common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, is also discussed. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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11 pages, 475 KiB  
Review
Modulating mTOR Signaling as a Promising Therapeutic Strategy for Atherosclerosis
by Anastasia V. Poznyak, Vasily N. Sukhorukov, Alexander Zhuravlev, Nikolay A. Orekhov, Vladislav Kalmykov and Alexander N. Orekhov
Int. J. Mol. Sci. 2022, 23(3), 1153; https://doi.org/10.3390/ijms23031153 - 21 Jan 2022
Cited by 12 | Viewed by 2601
Abstract
For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of [...] Read more.
For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of gaps remain in our understanding of the pathogenesis of atherosclerosis, and only their closure will bring us closer to understanding the causes of the disease at the cellular and molecular levels and, accordingly, to the development of an effective treatment. One of the seemingly well-studied elements of atherogenesis is the mTOR signaling pathway. However, more and more new details are still being clarified. Therapeutic strategies associated with rapamycin have worked well in a number of different diseases, and there is every reason to believe that targeting components of the mTOR pathway may pay off in atherosclerosis as well. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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12 pages, 828 KiB  
Review
Cholesterol in the Cell Membrane—An Emerging Player in Atherogenesis
by Karel Paukner, Ivana Králová Lesná and Rudolf Poledne
Int. J. Mol. Sci. 2022, 23(1), 533; https://doi.org/10.3390/ijms23010533 - 04 Jan 2022
Cited by 19 | Viewed by 5762
Abstract
Membrane cholesterol is essential for cell membrane properties, just as serum cholesterol is important for the transport of molecules between organs. This review focuses on cholesterol transport between lipoproteins and lipid rafts on the surface of macrophages. Recent studies exploring this mechanism and [...] Read more.
Membrane cholesterol is essential for cell membrane properties, just as serum cholesterol is important for the transport of molecules between organs. This review focuses on cholesterol transport between lipoproteins and lipid rafts on the surface of macrophages. Recent studies exploring this mechanism and recognition of the central dogma—the key role of macrophages in cardiovascular disease—have led to the notion that this transport mechanism plays a major role in the pathogenesis of atherosclerosis. The exact molecular mechanism of this transport remains unclear. Future research will improve our understanding of the molecular and cellular bases of lipid raft-associated cholesterol transport. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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29 pages, 5792 KiB  
Review
New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses
by Michael Maes, Nikita G. Nikiforov, Kitiporn Plaimas, Apichat Suratanee, Daniela Frizon Alfieri and Edna Maria Vissoci Reiche
Int. J. Mol. Sci. 2021, 22(22), 12108; https://doi.org/10.3390/ijms222212108 - 09 Nov 2021
Cited by 7 | Viewed by 3607
Abstract
This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB [...] Read more.
This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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18 pages, 857 KiB  
Review
Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis
by Diana Salnikova, Varvara Orekhova, Andrey Grechko, Antonina Starodubova, Evgeny Bezsonov, Tatyana Popkova and Alexander Orekhov
Int. J. Mol. Sci. 2021, 22(16), 8990; https://doi.org/10.3390/ijms22168990 - 20 Aug 2021
Cited by 42 | Viewed by 4120
Abstract
Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects [...] Read more.
Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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18 pages, 599 KiB  
Review
The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets
by Siarhei A. Dabravolski, Nikita G. Nikiforov, Antonina V. Starodubova, Tatyana V. Popkova and Alexander N. Orekhov
Int. J. Mol. Sci. 2021, 22(16), 8770; https://doi.org/10.3390/ijms22168770 - 16 Aug 2021
Cited by 21 | Viewed by 3860
Abstract
Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and [...] Read more.
Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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15 pages, 725 KiB  
Review
Immunity in Atherosclerosis: Focusing on T and B Cells
by Anastasia V. Poznyak, Evgeny E. Bezsonov, Tatyana V. Popkova, Antonina V. Starodubova and Alexander N. Orekhov
Int. J. Mol. Sci. 2021, 22(16), 8379; https://doi.org/10.3390/ijms22168379 - 04 Aug 2021
Cited by 20 | Viewed by 2626
Abstract
Atherosclerosis is the major cause of the development of cardiovascular disease, which, in turn, is one of the leading causes of mortality worldwide. From the point of view of pathogenesis, atherosclerosis is an extremely complex disease. A huge variety of processes, such as [...] Read more.
Atherosclerosis is the major cause of the development of cardiovascular disease, which, in turn, is one of the leading causes of mortality worldwide. From the point of view of pathogenesis, atherosclerosis is an extremely complex disease. A huge variety of processes, such as violation of mitophagy, oxidative stress, damage to the endothelium, and others, are involved in atherogenesis; however, the main components of atherogenesis are considered to be inflammation and alterations of lipid metabolism. In this review, we want to focus on inflammation, and more specifically on the cellular elements of adaptive immunity, T and B cells. It is known that various T cells are widely represented directly in atherosclerotic plaques, while B cells can be found, for example, in the adventitia layer. Of course, such widespread and well-studied cells have attracted attention as potential therapeutic targets for the treatment of atherosclerosis. Various approaches have been developed and tested for their efficacy. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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14 pages, 674 KiB  
Review
The Role of Mitochondrial Mutations and Chronic Inflammation in Diabetes
by Siarhei A. Dabravolski, Varvara A. Orekhova, Mirza S. Baig, Evgeny E. Bezsonov, Antonina V. Starodubova, Tatyana V. Popkova and Alexander N. Orekhov
Int. J. Mol. Sci. 2021, 22(13), 6733; https://doi.org/10.3390/ijms22136733 - 23 Jun 2021
Cited by 23 | Viewed by 4346
Abstract
Diabetes mellitus and related disorders significantly contribute to morbidity and mortality worldwide. Despite the advances in the current therapeutic methods, further development of anti-diabetic therapies is necessary. Mitochondrial dysfunction is known to be implicated in diabetes development. Moreover, specific types of mitochondrial diabetes [...] Read more.
Diabetes mellitus and related disorders significantly contribute to morbidity and mortality worldwide. Despite the advances in the current therapeutic methods, further development of anti-diabetic therapies is necessary. Mitochondrial dysfunction is known to be implicated in diabetes development. Moreover, specific types of mitochondrial diabetes have been discovered, such as MIDD (maternally inherited diabetes and deafness) and DAD (diabetes and Deafness). Hereditary mitochondrial disorders are caused by certain mutations in the mitochondrial DNA (mtDNA), which encodes for a substantial part of mitochondrial proteins and mitochondrial tRNA necessary for mitochondrial protein synthesis. Study of mtDNA mutations is challenging because the pathogenic phenotype associated with such mutations depends on the level of its heteroplasmy (proportion of mtDNA copies carrying the mutation) and can be tissue-specific. Nevertheless, modern sequencing methods have allowed describing and characterizing a number of mtDNA mutations associated with human disorders, and the list is constantly growing. In this review, we provide a list of mtDNA mutations associated with diabetes and related disorders and discuss the mechanisms of their involvement in the pathology development. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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11 pages, 276 KiB  
Review
ACE2 Is an Adjacent Element of Atherosclerosis and COVID-19 Pathogenesis
by Anastasia V. Poznyak, Evgeny E. Bezsonov, Ali H. Eid, Tatyana V. Popkova, Ludmila V. Nedosugova, Antonina V. Starodubova and Alexander N. Orekhov
Int. J. Mol. Sci. 2021, 22(9), 4691; https://doi.org/10.3390/ijms22094691 - 29 Apr 2021
Cited by 9 | Viewed by 2757
Abstract
COVID-19 is a highly contagious new infection caused by the single-stranded RNA Sars-CoV-2 virus. For the first time, this infection was recorded in December 2019 in the Chinese province of Wuhan. The virus presumably crossed the interspecies barrier and passed to humans from [...] Read more.
COVID-19 is a highly contagious new infection caused by the single-stranded RNA Sars-CoV-2 virus. For the first time, this infection was recorded in December 2019 in the Chinese province of Wuhan. The virus presumably crossed the interspecies barrier and passed to humans from a bat. Initially, the disease was considered exclusively in the context of damage to the respiratory system, but it quickly became clear that the disease also entails serious consequences from various systems, including the cardiovascular system. Among these consequences are myocarditis, myocardial damage, subsequent heart failure, myocardial infarction, and Takotsubo syndrome. On the other hand, clinical data indicate that the presence of chronic diseases in a patient aggravates the course and outcome of coronavirus infection. In this context, the relationship between COVID-19 and atherosclerosis, a condition preceding cardiovascular disease and other disorders of the heart and blood vessels, is particularly interesting. The renin-angiotensin system is essential for the pathogenesis of both coronavirus disease and atherosclerosis. In particular, it has been shown that ACE2, an angiotensin-converting enzyme 2, plays a key role in Sars-CoV-2 infection due to its receptor activity. It is noteworthy that this enzyme is important for the normal functioning of the cardiovascular system. Disruptions in its production and functioning can lead to various disorders, including atherosclerosis. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)

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17 pages, 32123 KiB  
Opinion
Opinion: On the Way towards the New Paradigm of Atherosclerosis
by Alexander A. Mironov and Galina V. Beznoussenko
Int. J. Mol. Sci. 2022, 23(4), 2152; https://doi.org/10.3390/ijms23042152 - 15 Feb 2022
Cited by 7 | Viewed by 2486
Abstract
Atherosclerosis is a multicausal disease characterized by the formation of cholesterol-containing plaque in the pronounced intima nearest to the heart’s elastic-type arteries that have high levels of blood circulation. Plaques are formed due to arterial pressure-induced damage to the endothelium in areas of [...] Read more.
Atherosclerosis is a multicausal disease characterized by the formation of cholesterol-containing plaque in the pronounced intima nearest to the heart’s elastic-type arteries that have high levels of blood circulation. Plaques are formed due to arterial pressure-induced damage to the endothelium in areas of turbulent blood flow. It is found in the majority of the Western population, including young people. This denies the monogenic mechanism of atherogenesis. In 1988, Orekhov et al. and Kawai et al. discovered that the presence of atherogenic (modified, including oxidized ones) LDLs is necessary for atherogenesis. On the basis of our discovery, suggesting that the overloading of enterocytes with lipids could lead to the formation of modified LDLs, we proposed a new hypothesis explaining the main factors of atherogenesis. Indeed, when endothelial cells are damaged and then pass through the G2 phase of their cell cycle they secrete proteins into their basement membrane. This leads to thickening of the basement membrane and increases its affinity to LDL especially for modified ones. When the enterocyte transcytosis pathway is overloaded with fat, very large chylomicrons are formed, which have few sialic acids, circulate in the blood for a long time, undergo oxidation, and can induce the production of autoantibodies. It is the sialic acids that shield the short forks of the polysaccharide chains to which autoantibodies are produced. Here, these data are evaluated from the point of view of our new model. Full article
(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)
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