International Journal of Molecular Sciences

Editorial

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4 pages, 191 KiB

Open AccessEditorial

Not All Quiet on the Atherosclerosis Front

by Katrin Schäfer

Int. J. Mol. Sci. 2023, 24(8), 7527; https://doi.org/10.3390/ijms24087527 - 19 Apr 2023

Viewed by 878

Abstract

In recent decades, research has identified the key cellular processes that take place during atherosclerotic plaque development and progression, including endothelial dysfunction, inflammation and lipoprotein oxidation, which result in macrophage and mural cell activation, death and necrotic core formation [...] Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

Research

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14 pages, 4343 KiB

Open AccessArticle

Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation

by Paul Marczynski, Myriam Meineck, Ning Xia, Huige Li, Daniel Kraus, Wilfried Roth, Tamara Möckel, Simone Boedecker, Andreas Schwarting and Julia Weinmann-Menke

Int. J. Mol. Sci. 2021, 22(5), 2291; https://doi.org/10.3390/ijms22052291 - 25 Feb 2021

Cited by 13 | Viewed by 2881

Abstract

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable [...] Read more.

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. Methods: Here we investigated whether MRL-Fas^lpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Fas^lpr, MRL-++, and previously generated Il6^−/− MRL-Fas^lpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. Results: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. Conclusion: Our findings demonstrate that the MRL-Fas^lpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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21 pages, 4170 KiB

Open AccessArticle

Calciprotein Particles Cause Endothelial Dysfunction under Flow

by Daria Shishkova, Victoria Markova, Maxim Sinitsky, Anna Tsepokina, Elena Velikanova, Leo Bogdanov, Tatiana Glushkova and Anton Kutikhin

Int. J. Mol. Sci. 2020, 21(22), 8802; https://doi.org/10.3390/ijms21228802 - 20 Nov 2020

Cited by 22 | Viewed by 2557

Abstract

Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on [...] Read more.

Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on endothelial cells (ECs) under flow. Here, we applied a flow culture system, where human arterial ECs were co-incubated with CPPs for 4 h, and a normolipidemic and normotensive rat model (10 daily intravenous injections of CPPs) to simulate the scenario occurring in vivo in the absence of confounding cardiovascular risk factors. Pathogenic effects of CPPs were investigated by RT-qPCR and Western blotting profiling of the endothelial lysate. CPPs were internalised within 1 h of circulation, inducing adhesion of peripheral blood mononuclear cells to ECs. Molecular profiling revealed that CPPs stimulated the expression of pro-inflammatory cell adhesion molecules VCAM1 and ICAM1 and upregulated transcription factors of endothelial-to-mesenchymal transition (Snail, Slug and Twist1). Furthermore, exposure to CPPs reduced the production of atheroprotective transcription factors KLF2 and KLF4 and led to YAP1 hypophosphorylation, potentially disturbing the mechanisms responsible for the proper endothelial mechanotransduction. Taken together, our results suggest the ability of CPPs to initiate endothelial dysfunction at physiological flow conditions. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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10 pages, 1878 KiB

Open AccessArticle

Angiotensin II Infusion Leads to Aortic Dissection in LRP8 Deficient Mice

by Jeremy Lagrange, Stefanie Finger, Sabine Kossmann, Venkata Garlapati, Wolfram Ruf and Philip Wenzel

Int. J. Mol. Sci. 2020, 21(14), 4916; https://doi.org/10.3390/ijms21144916 - 12 Jul 2020

Cited by 6 | Viewed by 2938

Abstract

Myeloid cells are crucial for the development of vascular inflammation. Low-density lipoprotein receptor-related protein 8 (LRP8) or Apolipoprotein E receptor 2 (ApoER2), is expressed by macrophages, endothelial cells and platelets and has been implicated in the development of cardiovascular diseases. Our aim was [...] Read more.

Myeloid cells are crucial for the development of vascular inflammation. Low-density lipoprotein receptor-related protein 8 (LRP8) or Apolipoprotein E receptor 2 (ApoER2), is expressed by macrophages, endothelial cells and platelets and has been implicated in the development of cardiovascular diseases. Our aim was to evaluate the role of LRP8, in particular from immune cells, in the development of vascular inflammation. Methods. LRP8^+/+ and LRP8^−/− mice (on B6;129S background) were infused with angiotensin II (AngII, 1 mg/kg/day for 7 to 28 day) using osmotic minipumps. Blood pressure was recorded using tail cuff measurements. Vascular reactivity was assessed in isolated aortic segments. Leukocyte activation and infiltration were assessed by flow cytometry of aortic tissue and intravital videomicroscopy imaging. Histological analysis of aortic sections was conducted using sirius red staining. Results. AngII infusion worsened endothelial-dependent vascular relaxation and immune cells rolling and adherence to the carotid artery in both LRP8^+/+ as well as LRP8^−/− mice. However, only LRP8^−/− mice demonstrated a drastically increased mortality rate in response to AngII due to aortic dissection. Bone marrow transplantation revealed that chimeras with LRP8 deficient myeloid cells phenocopied LRP8^−/− mice. Conclusion. AngII-infused LRP8 deficient mice could be a useful animal model to study aortic dissection reflecting the lethality of this disease in humans. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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Review

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17 pages, 319 KiB

Open AccessReview

Proteomic Studies of Blood and Vascular Wall in Atherosclerosis

by Ekaterina Mikhailovna Stakhneva, Evgeniia Vitalievna Striukova and Yulia Igorevna Ragino

Int. J. Mol. Sci. 2021, 22(24), 13267; https://doi.org/10.3390/ijms222413267 - 9 Dec 2021

Cited by 8 | Viewed by 3460

Abstract

The review is devoted to the analysis of literature data related to the role of proteomic studies in the study of atherosclerotic cardiovascular diseases. Diagnosis of patients with atherosclerotic plaques before clinical manifestations is an arduous task. The review presents the results of [...] Read more.

The review is devoted to the analysis of literature data related to the role of proteomic studies in the study of atherosclerotic cardiovascular diseases. Diagnosis of patients with atherosclerotic plaques before clinical manifestations is an arduous task. The review presents the results of research on the new proteomic potential biomarkers of coronary heart disease, coronary atherosclerosis, acute coronary syndrome, myocardial infarction, carotid artery atherosclerosis. Also, the analysis of literature data on proteomic studies of the vascular wall was carried out. To assess the involvement of proteins in the pathological process of atherosclerosis, it is important to investigate the specific relationships between proteins in the arteries, expression and concentration of proteins. The development of proteomic technologies has made it possible to analyse the number of proteins associated with the development of the disease. Analysis of the proteomic profile of the vascular wall in atherosclerosis can help to detect possible diagnostically significant protein structures or potential biomarkers of the disease and develop novel approaches to the diagnosis of atherosclerosis and its complications. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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33 pages, 1404 KiB

Open AccessReview

Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence

by Konstantinos Zifkos, Christophe Dubois and Katrin Schäfer

Int. J. Mol. Sci. 2021, 22(17), 9317; https://doi.org/10.3390/ijms22179317 - 27 Aug 2021

Cited by 38 | Viewed by 4563

Abstract

Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it [...] Read more.

Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it has become evident that EV formation, secretion and uptake represent important mechanisms of intercellular communication and exchange of a wide variety of molecules, with relevance in both physiological and pathological situations. The putative role of EVs in hemostasis and thrombosis is supported by clinical and experimental studies unraveling how these cell-derived structures affect clot formation (and resolution). From those studies, it has become clear that the prothrombotic effects of EVs are not restricted to the exposure of tissue factor (TF) and phosphatidylserines (PS), but also involve multiplication of procoagulant surfaces, cross-linking of different cellular players at the site of injury and transfer of activation signals to other cell types. Here, we summarize the existing and novel clinical and experimental evidence on the role and function of EVs during arterial and venous thrombus formation and how they may be used as biomarkers as well as therapeutic vectors. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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13 pages, 1127 KiB

Open AccessReview

Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

by Michal Kowara and Agnieszka Cudnoch-Jedrzejewska

Int. J. Mol. Sci. 2021, 22(7), 3513; https://doi.org/10.3390/ijms22073513 - 29 Mar 2021

Cited by 26 | Viewed by 3985

Abstract

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, [...] Read more.

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years—in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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19 pages, 1431 KiB

Open AccessReview

Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

by Andy W. C. Man, Huige Li and Ning Xia

Int. J. Mol. Sci. 2021, 22(2), 676; https://doi.org/10.3390/ijms22020676 - 12 Jan 2021

Cited by 41 | Viewed by 7750

Abstract

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings [...] Read more.

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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20 pages, 1513 KiB

Open AccessReview

Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability

by Wioletta Olejarz, Dominika Łacheta and Grażyna Kubiak-Tomaszewska

Int. J. Mol. Sci. 2020, 21(11), 3946; https://doi.org/10.3390/ijms21113946 - 31 May 2020

Cited by 113 | Viewed by 6245

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms [...] Read more.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms and the expression of MMPs in both the atherosclerotic plaque and plasma was shown. They are independent predictors of atherosclerotic plaque instability in stable coronary heart disease (CHD) patients. Increased levels of MMPs in patients with advanced cardiovascular disease (CAD) and acute coronary syndrome (ACS) was associated with future risk of cardiovascular events. These data confirm that MMPs may be biomarkers in plaque instability as they target in potential drug therapies for atherosclerosis. They provide important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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14 pages, 1263 KiB

Open AccessReview

Exogenous NO Therapy for the Treatment and Prevention of Atherosclerosis

by Tommaso Gori

Int. J. Mol. Sci. 2020, 21(8), 2703; https://doi.org/10.3390/ijms21082703 - 13 Apr 2020

Cited by 23 | Viewed by 5760

Abstract

Amyl nitrite was introduced in 1867 as the first molecule of a new class of agents for the treatment of angina pectoris. In the following 150 years, the nitric oxide pathway has been the subject of a number of pharmacological approaches, particularly since [...] Read more.

Amyl nitrite was introduced in 1867 as the first molecule of a new class of agents for the treatment of angina pectoris. In the following 150 years, the nitric oxide pathway has been the subject of a number of pharmacological approaches, particularly since when this elusive mediator was identified as one of the most important modulators of vascular homeostasis beyond vasomotion, including platelet function, inflammation, and atherogenesis. While having potent antianginal and antiischemic properties, however, nitric oxide donors are also not devoid of side effects, including the induction of tolerance, and, as shown in the last decade, of oxidative stress and endothelial dysfunction. In turn, endothelial dysfunction is itself felt to be involved in all stages of atherogenesis, from the development of fatty streaks to plaque rupture and thrombosis. In the present review, we summarize the agents that act on the nitric oxide pathway, with a particular focus on their potentially beneficial antiatherosclerotic and unwanted pro-atherosclerotic effects. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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Other

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12 pages, 3609 KiB

Open AccessBrief Report

The Commensal Microbiota Enhances ADP-Triggered Integrin α_IIbβ₃ Activation and von Willebrand Factor-Mediated Platelet Deposition to Type I Collagen

by Klytaimnistra Kiouptsi, Sven Jäckel, Eivor Wilms, Giulia Pontarollo, Jana Winterstein, Cornelia Karwot, Kathrin Groß, Kerstin Jurk and Christoph Reinhardt

Int. J. Mol. Sci. 2020, 21(19), 7171; https://doi.org/10.3390/ijms21197171 - 28 Sep 2020

Cited by 11 | Viewed by 2803

Abstract

The commensal microbiota is a recognized enhancer of arterial thrombus growth. While several studies have demonstrated the prothrombotic role of the gut microbiota, the molecular mechanisms promoting arterial thrombus growth are still under debate. Here, we demonstrate that germ-free (GF) mice, which from [...] Read more.

The commensal microbiota is a recognized enhancer of arterial thrombus growth. While several studies have demonstrated the prothrombotic role of the gut microbiota, the molecular mechanisms promoting arterial thrombus growth are still under debate. Here, we demonstrate that germ-free (GF) mice, which from birth lack colonization with a gut microbiota, show diminished static deposition of washed platelets to type I collagen compared with their conventionally raised (CONV-R) counterparts. Flow cytometry experiments revealed that platelets from GF mice show diminished activation of the integrin α_IIbβ₃ (glycoprotein IIbIIIa) when activated by the platelet agonist adenosine diphosphate (ADP). Furthermore, washed platelets from Toll-like receptor-2 (Tlr2)-deficient mice likewise showed impaired static deposition to the subendothelial matrix component type I collagen compared with wild-type (WT) controls, a process that was unaffected by GPIbα-blockade but influenced by von Willebrand factor (VWF) plasma levels. Collectively, our results indicate that microbiota-triggered steady-state activation of innate immune pathways via TLR2 enhances platelet deposition to subendothelial matrix molecules. Our results link host colonization status with the ADP-triggered activation of integrin α_IIbβ₃, a pathway promoting platelet deposition to the growing thrombus. Full article

(This article belongs to the Special Issue Molecular Research on Arteriosclerosis and Thrombosis)

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