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Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 33934

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Dr. Ida Daniela Perrotta

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Department of Biology, Ecology and Earth Sciences, Centre for Microscopy and Microanalysis (CM2), University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
Interests: atherosclerosis; vascular smooth muscle cell; inflammation; endothelium; cell senescence; apoptosis; lipid metabolism; oxidative stress; nitric oxide; exosomes; vascular calcification; cytokines; growth factors
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Dear Colleagues,

Although studies on the molecular biology of atherogenesis have become the focus of modern atherosclerosis research, the multifactorial pathogenesis of the disease has not been fully elucidated to date. Atherosclerosis is a fibroproliferative disease that proceeds through a series of pathological events involving the inflammatory and immune systems as well as the different types of cells and matrix proteins of the vascular wall. The disease is accompanied by the subendothelial accumulation of lipids and fibrous connective tissue, the phenotypic modulation of SMCs, and the migration of a group of cells, notably monocytes and T cells, through the vascular endothelium in response to inflammation. Along with the traditional cardiovascular risk factors, many other molecular determinants have a role in the appearance, progression, and complication of the disease. Inflammatory cytokines, growth factors, markers of oxidative stress, cell death signals, and mediators of vascular tone all participate in the inflammatory response of atherosclerosis via multiple intricate pathways. Also, arterial wall calcification is considered a direct marker of atherosclerotic disease, yet its underlying molecular mechanisms remain to be elucidated. Other important contributors to atherosclerosis are the exosomes and their miRNAs whose role and interactions with the microenvironment of the plaque can be exploited therapeutically.

This Special Issue on “Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0” welcomes original research articles and reviews in the field, with a focus on (but not limited to) the molecular mechanisms mediating vascular inflammation, endothelial dysfunction, SMC biology, immune-metabolic interactions, apoptosis, cell-to-cell communication, lipid metabolism, and vascular cell senescence.

Dr. Ida Daniela Perrotta
Guest Editor

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Keywords

atherosclerosis
vascular smooth muscle cell
inflammation
endothelium
cell senescence
apoptosis
lipid metabolism
oxidative stress
nitric oxide
exosomes
vascular calcification
cytokines
growth factors

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Research

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13 pages, 1569 KiB

Open AccessArticle

Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism

by Maria Pia Adorni, Bianca Papotti, Maria Orietta Borghi, Elena Raschi, Francesca Zimetti, Franco Bernini, Pier Luigi Meroni and Nicoletta Ronda

Int. J. Mol. Sci. 2023, 24(16), 12571; https://doi.org/10.3390/ijms241612571 - 8 Aug 2023

Cited by 5 | Viewed by 1586

Abstract

The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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17 pages, 6112 KiB

Open AccessArticle

Novel Tools for Comprehensive Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants

by Jacek Jasiecki, Monika Targońska, Anna Janaszak-Jasiecka, Magdalena Chmara, Monika Żuk, Leszek Kalinowski, Krzysztof Waleron and Bartosz Wasąg

Int. J. Mol. Sci. 2023, 24(14), 11435; https://doi.org/10.3390/ijms241411435 - 14 Jul 2023

Cited by 1 | Viewed by 2956

Abstract

Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused mainly by substitutions in the low-density lipoprotein receptor (LDLR) gene, leading to an increased risk of premature cardiovascular diseases. Tremendous advances in sequencing techniques have resulted in the discovery of more than 3000 variants of the LDLR gene, but not all of them are clinically relevant. Therefore, functional studies of selected variants are needed for their proper classification. Here, a single-cell, kinetic, fluorescent LDL uptake assay was applied for the functional analysis of LDLR variants in a model of an LDLR-deficient human cell line. An LDLR-defective HEK293T cell line was established via a CRISPR/Cas9-mediated luciferase–puromycin knock-in. The expressing vector with the LDLR gene under the control of the regulated promoter and with a reporter gene has been designed to overproduce LDLR variants in the host cell. Moreover, an LDLR promoter–luciferase knock-in reporter system has been created in the human cell line to study transcriptional regulation of the LDLR gene, which can serve as a simple tool for screening and testing new HMG CoA reductase-inhibiting drugs for atherosclerosis therapy. The data presented here demonstrate that the obtained LDLR-deficient human cell line HEK293T-ldlrG1 and the dedicated pTetRedLDLRwt expression vector are valuable tools for studying LDL internalization and functional analysis of LDLR and its genetic variants. Using appropriate equipment, LDL uptake to a single cell can be measured in real time. Moreover, the luciferase gene knock-in downstream of the LDLR promotor allows the study of promoter regulation in response to diverse conditions or drugs. An analysis of four known LDLR variants previously classified as pathogenic and benign was performed to validate the LDLR-expressing system described herein with the dedicated LDLR-deficient human cell line, HEK293T-ldlrG1. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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13 pages, 3475 KiB

Open AccessArticle

Detection of Early Endothelial Dysfunction by Optoacoustic Tomography

by Carsten Höltke, Leonie Enders, Miriam Stölting, Christiane Geyer, Max Masthoff, Michael T. Kuhlmann, Moritz Wildgruber and Anne Helfen

Int. J. Mol. Sci. 2023, 24(10), 8627; https://doi.org/10.3390/ijms24108627 - 11 May 2023

Viewed by 1758

Abstract

Variations in vascular wall shear stress are often presumed to result in the formation of atherosclerotic lesions at specific arterial regions, where continuous laminar flow is disturbed. The influences of altered blood flow dynamics and oscillations on the integrity of endothelial cells and the endothelial layer have been extensively studied in vitro and in vivo. Under pathological conditions, the Arg-Gly-Asp (RGD) motif binding integrin α_vβ₃ has been identified as a relevant target, as it induces endothelial cell activation. Animal models for in vivo imaging of endothelial dysfunction (ED) mainly rely on genetically modified knockout models that develop endothelial damage and atherosclerotic plaques upon hypercholesterolemia (ApoE^−/− and LDLR^−/−), thereby depicting late-stage pathophysiology. The visualization of early ED, however, remains a challenge. Therefore, a carotid artery cuff model of low and oscillating shear stress was applied in CD-1 wild-type mice, which should be able to show the effects of altered shear stress on a healthy endothelium, thus revealing alterations in early ED. Multispectral optoacoustic tomography (MSOT) was assessed as a non-invasive and highly sensitive imaging technique for the detection of an intravenously injected RGD-mimetic fluorescent probe in a longitudinal (2–12 weeks) study after surgical cuff intervention of the right common carotid artery (RCCA). Images were analyzed concerning the signal distribution upstream and downstream of the implanted cuff, as well as on the contralateral side as a control. Subsequent histological analysis was applied to delineate the distribution of relevant factors within the carotid vessel walls. Analysis revealed a significantly enhanced fluorescent signal intensity in the RCCA upstream of the cuff compared to the contralateral healthy side and the downstream region at all time points post-surgery. The most obvious differences were recorded at 6 and 8 weeks after implantation. Immunohistochemistry revealed a high degree of α_v-positivity in this region of the RCCA, but not in the left common carotid artery (LCCA) or downstream of the cuff. In addition, macrophages could be detected by CD68 immunohistochemistry in the RCCA, showing ongoing inflammatory processes. In conclusion, MSOT is capable of delineating alterations in endothelial cell integrity in vivo in the applied model of early ED, where an elevated expression of integrin α_vβ₃ was detected within vascular structures. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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22 pages, 3038 KiB

Open AccessArticle

Immunophenotyping of Monocyte Migration Markers and Therapeutic Effects of Selenium on IL-6 and IL-1β Cytokine Axes of Blood Mononuclear Cells in Preoperative and Postoperative Coronary Artery Disease Patients

by Max Wacker, Anna Ball, Hans-Dietmar Beer, Ingo Schmitz, Katrin Borucki, Faranak Azizzadeh, Maximilian Scherner, George Awad, Jens Wippermann and Priya Veluswamy

Int. J. Mol. Sci. 2023, 24(8), 7198; https://doi.org/10.3390/ijms24087198 - 13 Apr 2023

Cited by 3 | Viewed by 1987

Abstract

Multivessel coronary artery disease (CAD) is characterized by underlying chronic vascular inflammation and occlusion in the coronary arteries, where these patients undergo coronary artery bypass grafting (CABG). Since post-cardiotomy inflammation is a well known phenomenon after CABG, attenuation of this inflammation is required to reduce perioperative morbidity and mortality. In this study, we aimed to phenotype circulating frequencies and intensities of monocyte subsets and monocyte migration markers, respectively, and to investigate the plasma level of inflammatory cytokines and chemokines between preoperative and postoperative CAD patients and later, to intervene the inflammation with sodium selenite. We found a higher amplitude of inflammation, postoperatively, in terms of CCR1^high monocytes and significantly increased pro-inflammatory cytokines, IL-6, IL-8, and IL-1RA. Further, in vitro intervention with selenium displayed mitigating effects on the IL-6/STAT-3 axis of mononuclear cells derived from postoperative CAD patients. In addition, in vitro selenium intervention significantly reduced IL-1β production as well as decreased cleaved caspase-1 (p20) activity by preoperative (when stimulated) as well as postoperative CAD mononuclear cells. Though TNF-α exhibited a positive correlation with blood troponin levels in postoperative CAD patients, there was no obvious effect of selenium on the TNF-α/NF-κB axis. In conclusion, anti-inflammatory selenium might be utilized to impede systemic inflammatory cytokine axes to circumvent aggravating atherosclerosis and further damage to the autologous bypass grafts during the post-surgical period. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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15 pages, 2049 KiB

Open AccessArticle

An Unexpected Enzyme in Vascular Smooth Muscle Cells: Angiotensin II Upregulates Cholesterol-25-Hydroxylase Gene Expression

by Kinga Bernadett Kovács, Laura Szalai, Pál Szabó, Janka Borbála Gém, Szilvia Barsi, Bence Szalai, Bernadett Perey-Simon, Gábor Turu, András Dávid Tóth, Péter Várnai, László Hunyady and András Balla

Int. J. Mol. Sci. 2023, 24(4), 3968; https://doi.org/10.3390/ijms24043968 - 16 Feb 2023

Cited by 1 | Viewed by 2719

Abstract

Angiotensin II (AngII) is a vasoactive peptide hormone, which, under pathological conditions, contributes to the development of cardiovascular diseases. Oxysterols, including 25-hydroxycholesterol (25-HC), the product of cholesterol-25-hydroxylase (CH25H), also have detrimental effects on vascular health by affecting vascular smooth muscle cells (VSMCs). We investigated AngII-induced gene expression changes in VSMCs to explore whether AngII stimulus and 25-HC production have a connection in the vasculature. RNA-sequencing revealed that Ch25h is significantly upregulated in response to AngII stimulus. The Ch25h mRNA levels were elevated robustly (~50-fold) 1 h after AngII (100 nM) stimulation compared to baseline levels. Using inhibitors, we specified that the AngII-induced Ch25h upregulation is type 1 angiotensin II receptor- and G_q/11 activity-dependent. Furthermore, p38 MAPK has a crucial role in the upregulation of Ch25h. We performed LC-MS/MS to identify 25-HC in the supernatant of AngII-stimulated VSMCs. In the supernatants, 25-HC concentration peaked 4 h after AngII stimulation. Our findings provide insight into the pathways mediating AngII-induced Ch25h upregulation. Our study elucidates a connection between AngII stimulus and 25-HC production in primary rat VSMCs. These results potentially lead to the identification and understanding of new mechanisms in the pathogenesis of vascular impairments. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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19 pages, 7911 KiB

Open AccessArticle

Effects of Berries, Phytochemicals, and Probiotics on Atherosclerosis through Gut Microbiota Modification: A Meta-Analysis of Animal Studies

by Leila Khalili, Ann Marie Centner and Gloria Salazar

Int. J. Mol. Sci. 2023, 24(4), 3084; https://doi.org/10.3390/ijms24043084 - 4 Feb 2023

Cited by 10 | Viewed by 4083

Abstract

Atherosclerosis is a major cause of death and disability. The beneficial effects of phytochemicals and probiotics on atherosclerosis have gained significant interest since these functional foods can improve inflammation, oxidative stress, and microbiome dysbiosis. The direct effect of the microbiome in atherosclerosis, however, needs further elucidation. The objective of this work was to investigate the effects of polyphenols, alkaloids, and probiotics on atherosclerosis using a meta-analysis of studies with mouse models of atherosclerosis. Identification of eligible studies was conducted through searches on PubMed, Embase, Web of Science, and Science Direct until November 2022. The results showed that phytochemicals reduced atherosclerosis, which was significant in male mice, but not in females. Probiotics, on the other hand, showed significant reductions in plaque in both sexes. Berries and phytochemicals modulated gut microbial composition by reducing the Firmicutes/Bacteroidetes (F/B) ratio and by upregulating health-promoting bacteria, including Akkermansia muciniphila. This analysis suggests that phytochemicals and probiotics can reduce atherosclerosis in animal models, with a potentially greater effect on male animals. Thus, consumption of functional foods rich in phytochemicals as well as probiotics are viable interventions to improve gut health and reduce plaque burden in patients suffering from cardiovascular disease (CVD). Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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14 pages, 283 KiB

Open AccessArticle

Moutan Cortex Extract Modulates Macrophage Activation via Lipopolysaccharide-Induced Calcium Signaling and ER Stress-CHOP Pathway

by Hyun-Ju Kim, Do-Hoon Kim and Wansu Park

Int. J. Mol. Sci. 2023, 24(3), 2062; https://doi.org/10.3390/ijms24032062 - 20 Jan 2023

Cited by 3 | Viewed by 2232

Abstract

Moutan Cortex, Paeonia suffruticosa root, has long been used as a medicine for the treatment of inflammatory diseases. The aim of this study was to evaluate the modulative properties of Moutan Cortex water extract (CP) on endoplasmic reticulum (ER) stress-related macrophage activation via the calcium-CHOP pathway. RAW 264.7 mouse macrophages were activated by lipopolysaccharide (LPS), and the levels of various inflammatory mediators from RAW 264.7 were evaluated. The multiplex cytokine assay was used to investigate both cytokines and growth factors, and RT-PCR was used to investigate the expressions of inflammation-related genes, such as CHOP. Data represent the levels of NO and cytosolic calcium in LPS-stimulated RAW 264.7 were significantly inhibited by CP as well as hydrogen peroxide (p < 0.05). Minutely, NO production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 97.32 ± 1.55%, 95.86 ± 2.26%, 94.64 ± 1.83%, and 92.69 ± 2.31% of the control value (LPS only), respectively (p < 0.05). Calcium release in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 18 h was 95.78 ± 1.64%, 95.41 ± 1.14%, 94.54 ± 2.76%, and 90.89 ± 3.34% of the control value, respectively (p < 0.05). Hydrogen peroxide production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 79.15 ± 7.16%, 63.83 ± 4.03%, 46.27 ± 4.38%, and 40.66 ± 4.03% of the control value, respectively (p < 0.05). It is interesting that the production of IL-6, TNF-α, G-CSF, MIP-1α, MIP-2, and M-CSF in LPS-stimulated RAW 264.7 were significantly inhibited by CP (p < 0.05), while the production of LIX, LIF, RANTES, and MIP-1β showed a meaningful decrease. CP at concentrations of 25, 50, 100, and 200 µg/mL significantly reduced the transcription of Chop, Camk2α, NOS, STAT1, STAT3, Ptgs2, Jak2, c-Jun, Fas, c-Fos, TLR3, and TLR9 in LPS-stimulated RAW 264.7 (p < 0.05). CP at concentrations of 25, 50, and 100 µg/mL significantly reduced the phosphorylation of STAT3, p38 MAPK, and IκB-α in LPS-stimulated RAW 264.7 (p < 0.05). These results suggest that CP might modulate macrophage activation via LPS-induced calcium signaling and the ER stress-CHOP pathway. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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17 pages, 4012 KiB

Open AccessReview

Hydrogen Sulfide and Oxygen Homeostasis in Atherosclerosis: A Systematic Review from Molecular Biology to Therapeutic Perspectives

by Constantin Munteanu

Int. J. Mol. Sci. 2023, 24(9), 8376; https://doi.org/10.3390/ijms24098376 - 6 May 2023

Cited by 7 | Viewed by 2819

Abstract

Atherosclerosis is a complex pathological condition marked by the accumulation of lipids in the arterial wall, leading to the development of plaques that can eventually rupture and cause thrombotic events. In recent years, hydrogen sulfide (H₂S) has emerged as a key mediator of cardiovascular homeostasis, with potential therapeutic applications in atherosclerosis. This systematic review highlights the importance of understanding the complex interplay between H₂S, oxygen homeostasis, and atherosclerosis and suggests that targeting H₂S signaling pathways may offer new avenues for treating and preventing this condition. Oxygen homeostasis is a critical aspect of cardiovascular health, and disruption of this balance can contribute to the development and progression of atherosclerosis. Recent studies have demonstrated that H₂S plays an important role in maintaining oxygen homeostasis by regulating the function of oxygen-sensing enzymes and transcription factors in vascular cells. H₂S has been shown to modulate endothelial nitric oxide synthase (eNOS) activity, which plays a key role in regulating vascular tone and oxygen delivery to tissues. The comprehensive analysis of the current understanding of H₂S in atherosclerosis can pave the way for future research and the development of new therapeutic strategies for this debilitating condition. PROSPERO ID: 417150. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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16 pages, 1238 KiB

Open AccessReview

PCSK9 as an Atherothrombotic Risk Factor

by Tadeja Sotler and Miran Šebeštjen

Int. J. Mol. Sci. 2023, 24(3), 1966; https://doi.org/10.3390/ijms24031966 - 19 Jan 2023

Cited by 13 | Viewed by 2990

Abstract

Disturbances in lipid metabolism are among the most important risk factors for atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein in lipid metabolism that is also involved in the production of inflammatory cytokines, endothelial dysfunction and aherosclerotic plaque development. Studies have shown a connection between PCSK9 and various indicators of inflammation. Signalling pathways that include PCSK9 play important role in the initiation and development of atherosclerotic lesions by inducing vascular inflammation. Studies so far have suggested that PCSK9 is associated with procoagulation, enhancing the development of atherosclerosis. Experimentally, it was also found that an increased concentration of PCSK9 significantly accelerated the apoptosis of endothelial cells and reduced endothelial function, which created conditions for the development of atherosclerosis. PCSK9 inhibitors can therefore improve clinical outcomes not only in a lipid-dependent manner, but also through lipid-independent pathways. The aim of our review was to shed light on the impact of PCSK9 on these factors, which are not directly related to low-density lipoprotein (LDL) cholesterol metabolism. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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17 pages, 943 KiB

Open AccessReview

Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?

by Marina Canyelles, Carla Borràs, Noemí Rotllan, Mireia Tondo, Joan Carles Escolà-Gil and Francisco Blanco-Vaca

Int. J. Mol. Sci. 2023, 24(3), 1940; https://doi.org/10.3390/ijms24031940 - 18 Jan 2023

Cited by 36 | Viewed by 9891

Abstract

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which—at least in part—could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 4.0)

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