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Neutrophils in Cardiovascular Diseases
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Neutrophils in Cardiovascular Diseases

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 17428

Special Issue Editor

Dr. Aldo Bonaventura

E-Mail Website
Guest Editor
Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Interests: cardiovascular disease; atherosclerosis; neutrophils; diabetes; obesity; pericarditis

Special Issue Information

Cardiovascular diseases remain the first cause of death all around the world and are mostly caused by atherosclerosis. In recent years, big achievements in the understanding of the pathophysiology of atherosclerosis took place. In this view, the CANTOS (Canakinumab Antiinflammatory Thrombosis Outcomes Study) trial finally confirmed the utmost role of inflammatory pathways in cardiovascular disease irrespective of lipids. Both innate and acquired immunity have been recognized to play a central role in determining most of the manifestations of the atherosclerotic disease. Following a big leap forward in the understanding of in neutrophil biology, we now that they behave as central actors in atherosclerosis through novel cellular processes, including neutrophil extracellular trap (NET) production and microvesicle release. Additionally, the impaired interaction of neutrophils with other cells, namely platelets, is a key mechanism leading to thrombo-inflammation, thus feeding vascular injury. Last but not least, neutrophil-derived biomarkers are considered as important mediators in these detrimental processes.

This Special Issue “Neutrophils in cardiovascular diseases” will focus on functions and processes neutrophils are involved in with regard to cardiovascular diseases. Authors are invited to submit original research and review papers addressing the topic of this Special Issue.

Dr. Aldo Bonaventura
Guest Editor

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

  • neutrophils
  • cardiovascular disease
  • atherosclerosis
  • platelets
  • myeloperoxidase
  • neutrophil extracellular traps
  • inflammation
  • myocardial infarction
  • ischemia/reperfusion injury
  • heart failure

Published Papers (5 papers)

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Research

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14 pages, 1606 KiB  
Article
Recombinant Tissue Plasminogen Activator (r-tPA) Induces In-Vitro Human Neutrophil Migration via Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1)
by Luca Liberale, Maria Bertolotto, Silvia Minetti, Paola Contini, Daniela Verzola, Pietro Ameri, Giorgio Ghigliotti, Aldo Pende, Giovanni G. Camici, Federico Carbone and Fabrizio Montecucco
Int. J. Mol. Sci. 2020, 21(19), 7014; https://doi.org/10.3390/ijms21197014 - 23 Sep 2020
Cited by 14 | Viewed by 3140
Abstract
Thrombolysis is the gold standard treatment for acute ischemic stroke. Besides its fibrinolytic role, recombinant tissue plasminogen activator (r-tPA) holds several non-fibrinolytic functions. Here, we investigated the potential role of r-tPA on human primary neutrophil migration in vitro. By means of modified Boyden [...] Read more.
Thrombolysis is the gold standard treatment for acute ischemic stroke. Besides its fibrinolytic role, recombinant tissue plasminogen activator (r-tPA) holds several non-fibrinolytic functions. Here, we investigated the potential role of r-tPA on human primary neutrophil migration in vitro. By means of modified Boyden chamber migration assay and checkerboard analysis we showed a dose-dependent chemotactic effect of r-TPA with a maximum effect reached by 0.03 mg/mL (0.003–1 mg/mL). Pre-incubation with MAP kinases inhibitors allowed the identification of PI3K/Akt, but not ERK1/2 as the intracellular pathway mediating the observed effects. Furthermore, by means of real-time PCR, immunocytochemistry and cytofluorimetry we demonstrated that the r-tPA receptor low density lipoprotein receptor-related protein 1 (LRP-1) is synthetized and expressed by neutrophils in response to r-tPA and TNF-α. Inhibition of LRP-1 by receptor-associated protein (RAP), prevented r-tPA-mediated F-actin polymerization, migration and signal through Akt but not ERK1/2. Lastly, also neutrophil degranulation in response to r-tPA seems to be mediated by LRP-1 under adhesion conditions. In conclusion, we show that r-tPA induces neutrophil chemotaxis through LRP-1/Akt pathway. Blunting r-tPA-mediated neutrophil activation might be beneficial as an adjuvant therapy to thrombolysis in this setting. Full article
(This article belongs to the Special Issue Neutrophils in Cardiovascular Diseases)
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19 pages, 1430 KiB  
Article
Increase of Neutrophil Activation Markers in Venous Thrombosis—Contribution of Circulating Activated Protein C
by Laura Martos, Julia Oto, Álvaro Fernández-Pardo, Emma Plana, María José Solmoirago, Fernando Cana, David Hervás, Santiago Bonanad, Fernando Ferrando, Francisco España, Silvia Navarro and Pilar Medina
Int. J. Mol. Sci. 2020, 21(16), 5651; https://doi.org/10.3390/ijms21165651 - 6 Aug 2020
Cited by 24 | Viewed by 2711
Abstract
Upon activation, neutrophils release their content through different mechanisms like degranulation and NETosis, thus prompting thrombosis. The natural anticoagulant activated protein C (APC) inhibits neutrophil NETosis and, consequently, this may lower the levels of neutrophil activation markers in plasma, further diminishing the thrombotic [...] Read more.
Upon activation, neutrophils release their content through different mechanisms like degranulation and NETosis, thus prompting thrombosis. The natural anticoagulant activated protein C (APC) inhibits neutrophil NETosis and, consequently, this may lower the levels of neutrophil activation markers in plasma, further diminishing the thrombotic risk exerted by this anticoagulant. We aimed to describe the status of markers of neutrophil activation in plasma of patients with venous thrombosis, their association with the thrombotic risk and the potential contribution of APC. We quantified three markers of neutrophil activation (cell-free DNA, calprotectin, and myeloperoxidase) in 253 patients with venous thromboembolism (VTE) in a stable phase (192 lower extremity VTE and 61 splanchnic vein thrombosis) and in 249 healthy controls. In them, we also quantified plasma APC, soluble endothelial protein C receptor (EPCR), and soluble thrombomodulin (TM), and we genotyped two genetic regulators of APC: the EPCR gene (PROCR) haplotypes (H) and the TM gene (THBD) c.1418C>T polymorphism. We found a significant increase in plasma cell-free DNA (p < 0.0001), calprotectin (p = 0.0001) and myeloperoxidase (p = 0.005) in VTE patients compared to controls. Furthermore, all three neutrophil activation markers were associated with an increase in the thrombotic risk. Cell-free DNA and calprotectin plasma levels were significantly correlated (Spearman r = 0.28; p < 0.0001). As expected, the natural anticoagulant APC was significantly decreased in VTE patients (p < 0.0001) compared to controls, what was mediated by its genetic regulators PROCR-H1, PROCR-H3, and THBD-c.1418T, and inversely correlated with cell-free DNA levels. This is the largest case-control study that demonstrates the increase in markers of neutrophil activation in vivo in VTE patients and their association with an increased thrombotic risk. This increase could be mediated by low APC levels and its genetic regulators, which could also increase NETosis, further enhancing thrombosis and inflammation. Full article
(This article belongs to the Special Issue Neutrophils in Cardiovascular Diseases)
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12 pages, 3393 KiB  
Article
Neutrophils Modulate Fibroblast Function and Promote Healing and Scar Formation after Murine Myocardial Infarction †
by Adelina Curaj, David Schumacher, Mihaela Rusu, Mareike Staudt, Xiaofeng Li, Sakine Simsekyilmaz, Vera Jankowski, Joachim Jankowski, Andreea Ramona Dumitraşcu, Derek J Hausenloy, Alexander Schuh and Elisa A. Liehn
Int. J. Mol. Sci. 2020, 21(10), 3685; https://doi.org/10.3390/ijms21103685 - 23 May 2020
Cited by 28 | Viewed by 3318
Abstract
Aim: Recruitment of neutrophils to the heart following acute myocardial infarction (MI) initiates inflammation and contributes to adverse post-infarct left ventricular (LV) remodeling. However, therapeutic inhibition of neutrophil recruitment into the infarct zone has not been beneficial in MI patients, suggesting a possible [...] Read more.
Aim: Recruitment of neutrophils to the heart following acute myocardial infarction (MI) initiates inflammation and contributes to adverse post-infarct left ventricular (LV) remodeling. However, therapeutic inhibition of neutrophil recruitment into the infarct zone has not been beneficial in MI patients, suggesting a possible dual role for neutrophils in inflammation and repair following MI. Here, we investigate the effect of neutrophils on cardiac fibroblast function following MI. Methods and Results: We found that co-incubating neutrophils with isolated cardiac fibroblasts enhanced the production of provisional extracellular matrix proteins and reduced collagen synthesis when compared to control or co-incubation with mononuclear cells. Furthermore, we showed that neutrophils are required to induce the transient up-regulation of transforming growth factor (TGF)-ß1 expression in fibroblasts, a key requirement for terminating the pro-inflammatory phase and allowing the reparatory phase to form a mature scar after MI. Conclusion: Neutrophils are essential for both initiation and termination of inflammatory events that control and modulate the healing process after MI. Therefore, one should exercise caution when testing therapeutic strategies to inhibit neutrophil recruitment into the infarct zone in MI patients. Full article
(This article belongs to the Special Issue Neutrophils in Cardiovascular Diseases)
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Review

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22 pages, 1659 KiB  
Review
The Neutrophil Secretome as a Crucial Link between Inflammation and Thrombosis
by María Amparo Blanch-Ruiz, Raquel Ortega-Luna, María Ángeles Martínez-Cuesta and Ángeles Álvarez
Int. J. Mol. Sci. 2021, 22(8), 4170; https://doi.org/10.3390/ijms22084170 - 17 Apr 2021
Cited by 19 | Viewed by 4073
Abstract
Cardiovascular diseases are a leading cause of death. Blood–cell interactions and endothelial dysfunction are fundamental in thrombus formation, and so further knowledge of the pathways involved in such cellular crosstalk could lead to new therapeutical approaches. Neutrophils are secretory cells that release well-known [...] Read more.
Cardiovascular diseases are a leading cause of death. Blood–cell interactions and endothelial dysfunction are fundamental in thrombus formation, and so further knowledge of the pathways involved in such cellular crosstalk could lead to new therapeutical approaches. Neutrophils are secretory cells that release well-known soluble inflammatory signaling mediators and other complex cellular structures whose role is not fully understood. Studies have reported that neutrophil extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) contribute to thrombosis. The objective of this review is to study the role of EVs and NETs as key factors in the transition from inflammation to thrombosis. The neutrophil secretome can promote thrombosis due to the presence of different factors in the EVs bilayer that can trigger blood clotting, and to the release of soluble mediators that induce platelet activation or aggregation. On the other hand, one of the main pathways by which NETs induce thrombosis is through the creation of a scaffold to which platelets and other blood cells adhere. In this context, platelet activation has been associated with the induction of NETs release. Hence, the structure and composition of EVs and NETs, as well as the feedback mechanism between the two processes that causes pathological thrombus formation, require exhaustive analysis to clarify their role in thrombosis. Full article
(This article belongs to the Special Issue Neutrophils in Cardiovascular Diseases)
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16 pages, 1386 KiB  
Review
The Role of Neutrophils in Hypertension
by Patricio Araos, Stefanny Figueroa and Cristián A. Amador
Int. J. Mol. Sci. 2020, 21(22), 8536; https://doi.org/10.3390/ijms21228536 - 12 Nov 2020
Cited by 28 | Viewed by 3721
Abstract
It is well accepted that the immune system and some cells from adaptive and innate immunity are necessary for the initiation/perpetuation of arterial hypertension (AH). However, whether neutrophils are part of this group remains debatable. There is evidence showing that the neutrophil/lymphocyte ratio [...] Read more.
It is well accepted that the immune system and some cells from adaptive and innate immunity are necessary for the initiation/perpetuation of arterial hypertension (AH). However, whether neutrophils are part of this group remains debatable. There is evidence showing that the neutrophil/lymphocyte ratio correlates with AH and is higher in non-dipper patients. On the other hand, the experimental neutrophil depletion in mice reduces basal blood pressure. Nevertheless, their participation in AH is still controversial. Apparently, neutrophils may modulate the microenvironment in blood vessels by increasing oxidative stress, favoring endothelial disfunction. In addition, neutrophils may contribute to the tissue infiltration of immune cells, secreting chemoattractant chemokines/cytokines and promoting the proinflammatory phenotype, leading to AH development. In this work, we discuss the potential role of neutrophils in AH by analyzing different mechanisms proposed from clinical and basic studies, with a perspective on cardiovascular and renal damages relating to the hypertensive phenotype. Full article
(This article belongs to the Special Issue Neutrophils in Cardiovascular Diseases)
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