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Cell Mar 2020Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an...
Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
Topics: Animals; Arteries; Bacterial Proteins; Blood Platelets; Cardiovascular Diseases; Death, Sudden, Cardiac; Gastrointestinal Microbiome; Glutamine; Humans; Male; Metabolome; Metabolomics; Mice; Myocardial Infarction; Platelet Activation; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Risk Factors; Stroke; Thrombosis
PubMed: 32142679
DOI: 10.1016/j.cell.2020.02.016 -
Circulation Dec 2021LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association...
BACKGROUND
LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that ) reduces LNK function and that LNK-deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic deficiency.
METHODS
We bred mice with combined deficiency of and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2).
RESULTS
-deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated platelets promoted increased NETosis when incubated with neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from platelets, as well as increased priming and response of neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in mice. We also showed increased NETosis when human induced pluripotent stem cell-derived ) neutrophils were incubated with ) platelet/megakaryocytes, but not in isogenic ) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2 mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic and clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with controls.
CONCLUSIONS
Hematopoietic deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.
Topics: Adaptor Proteins, Signal Transducing; Animals; Arteries; Blood Platelets; Mice; Mice, Knockout; Neutrophils; Oxidation-Reduction; Phospholipids; Platelet Aggregation; Thrombosis
PubMed: 34846914
DOI: 10.1161/CIRCULATIONAHA.121.056414 -
Circulation Research Apr 2020Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by... (Review)
Review
Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries and propagate and amplify the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (eg, MPO [myeloperoxidase] and various proteinases) but can gather other proteins found in blood (eg, tissue factor procoagulant). This review presents current concepts of neutrophil biology, the triggers to and mechanisms of NET formation, and the contribution of NETs to atherosclerosis and to thrombosis. We consider the use of markers of NETs in clinical studies. We aim here to integrate critically the experimental literature with the growing body of clinical information regarding NETs.
Topics: Animals; Arteries; Atherosclerosis; Biomarkers; Blood Coagulation; Extracellular Traps; Humans; Inflammation; Inflammation Mediators; Neutrophils; Plaque, Atherosclerotic; Reactive Oxygen Species; Rupture, Spontaneous; Signal Transduction; Thrombosis
PubMed: 32324499
DOI: 10.1161/CIRCRESAHA.120.315931 -
Arteriosclerosis, Thrombosis, and... Sep 2020Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different... (Review)
Review
Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different vascular territories. Acute coronary syndrome is a relatively common manifestation of coronary atherosclerotic disease, wherein the thrombosis occurs secondary to disruption (65%-75%) and erosion (25%-35%) of the fibrous caps of atheromatous plaques. The plaques associated with plaque rupture have large necrotic cores and thin and inflamed fibrous caps. However, the pathological manifestations of peripheral artery disease result from thrombosis regardless of the extent of atherosclerosis. Approximately 75% of peripheral arteries with significant stenosis demonstrate presence of thrombi, of which two-thirds have thrombi associated with insignificant atherosclerosis. The presence of obliterative thrombi in peripheral arteries of patients with critical limb ischemia in the absence of coronary artery-like lesions suggests a locally thrombogenic or remotely embolic basis of disease. Extensive calcification of the medial vascular layer is commonly observed. In this review, we have described and compared the pathological basis of coronary and peripheral artery disease in patients with acute coronary syndrome and critical limb ischemia. It is expected that pathogenetic characterization would allow for definition of strategic targets for superior management of peripheral artery disease.
Topics: Acute Coronary Syndrome; Arteries; Coronary Artery Disease; Coronary Vessels; Critical Illness; Disease Progression; Fibrinolytic Agents; Fibrosis; Humans; Ischemia; Peripheral Arterial Disease; Plaque, Atherosclerotic; Prognosis; Rupture, Spontaneous; Thrombosis
PubMed: 32673526
DOI: 10.1161/ATVBAHA.119.312864 -
Mayo Clinic Proceedings Feb 2021
Topics: Arteries; COVID-19; Humans; Thrombosis
PubMed: 33549245
DOI: 10.1016/j.mayocp.2020.12.009 -
JACC. Cardiovascular Interventions May 2021
Topics: Femoral Artery; Humans; Stents; Thrombosis; Treatment Outcome
PubMed: 34016413
DOI: 10.1016/j.jcin.2021.04.023 -
British Journal of Pharmacology Nov 2021Thrombosis contributes to one in four deaths worldwide and is the cause of a large proportion of mortality and morbidity. A reliable and rapid diagnosis of thrombosis... (Review)
Review
Thrombosis contributes to one in four deaths worldwide and is the cause of a large proportion of mortality and morbidity. A reliable and rapid diagnosis of thrombosis will allow for immediate therapy, thereby providing significant benefits to patients. Molecular imaging is a fast-growing and captivating area of research, in both preclinical and clinical applications. Major advances have been achieved by improvements in three central areas of molecular imaging: - (1) better markers for diseases, with increased sensitivity and selectivity, (2) optimised contrast agents with improved signal to noise ratio and (3), progress in scanner technologies with higher sensitivity and resolution. Clinically available imaging modalities used for molecular imaging include magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound, as well as nuclear imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). In the preclinical imaging field, optical (fluorescence and bioluminescent) molecular imaging has provided new mechanistic insights in the pathology of thromboembolic diseases. Overall, the advances in molecular imaging, driven by the collaboration of various scientific disciplines, have substantially contributed to an improved understanding of thrombotic disease and raise the exciting prospect of earlier diagnosis and individualised therapy for cardiovascular diseases. As such, these advances hold significant promise to be translated to clinical practice and ultimately to reduce mortality and morbidity in patients with thromboembolic diseases. LINKED ARTICLES: This article is part of a themed issue on Molecular imaging - visual themed issue. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.21/issuetoc.
Topics: Arteries; Biomarkers; Humans; Molecular Imaging; Thrombosis; Venous Thrombosis
PubMed: 34296431
DOI: 10.1111/bph.15635 -
Current Problems in Cardiology Oct 2022For more than 2 years, health care systems have been floundering in a massive crisis of coronavirus disease 2019 (COVID-19) pandemic. While acute respiratory distress... (Review)
Review
For more than 2 years, health care systems have been floundering in a massive crisis of coronavirus disease 2019 (COVID-19) pandemic. While acute respiratory distress syndrome is the main complication in patients with COVID-19, as the pandemic continues, more data about the nonrespiratory effects of the coronavirus is obtained, including developing Coagulopathy-related manifestations, in the form of venous and arterial thromboembolism. Although arterial thrombosis a rare complication of this disease, it proves to be an effective factor in the mortality and morbidity of COVID-19 patients. The pathophysiology of thrombosis reveals a complex relation between hemostasis and immune system that can be disrupted by COVID-19. Thrombectomy, anticoagulant therapy, and thrombolysis are the main treatments in these patients. In addition, appropriate thromboprophylaxis treatment should be considered in COVID-19 patients. In this article, we have successfully reviewed the arterial thrombotic events in patients reported around the world, including the diagnostic and management method of choice.
Topics: Anticoagulants; Arteries; COVID-19; Humans; SARS-CoV-2; Thrombosis; Venous Thromboembolism
PubMed: 34571103
DOI: 10.1016/j.cpcardiol.2021.100992 -
Current Opinion in Hematology Jan 2024Models of arterial thrombus formation represent a vital experimental tool to investigate platelet function and test novel antithrombotic drugs. This review highlights... (Review)
Review
PURPOSE OF REVIEW
Models of arterial thrombus formation represent a vital experimental tool to investigate platelet function and test novel antithrombotic drugs. This review highlights some of the recent advances in modelling thrombus formation in vitro and suggests potential future directions.
RECENT FINDINGS
Microfluidic devices and the availability of commercial chips in addition to enhanced accessibility of 3D printing has facilitated a rapid surge in the development of novel in-vitro thrombosis models. These include progression towards more sophisticated, 'vessel on a chip' models which incorporate vascular endothelial cells and smooth muscle cells. Other approaches include the addition of branches to the traditional single channel to yield an occlusive model; and developments in the adhesive coating of microfluidic chambers to better mimic the thrombogenic surface exposed following plaque rupture. Future developments in the drive to create more biologically relevant chambers could see a move towards the use of human placental vessels, perfused ex-vivo. However, further work is required to determine the feasibility and validity of this approach.
SUMMARY
Recent advances in thrombus formation models have significantly improved the pathophysiological relevance of in-vitro flow chambers to better reflect the in-vivo environment and provide a more translational platform to test novel antithrombotics.
Topics: Female; Pregnancy; Humans; Endothelial Cells; Placenta; Thrombosis; Arteries; Hemostasis
PubMed: 37823547
DOI: 10.1097/MOH.0000000000000789 -
Platelets May 2020A confluence of technological advances in genetic manipulation and molecular-based fluorescence imaging has led to the widespread adoption of laser injury models to... (Review)
Review
A confluence of technological advances in genetic manipulation and molecular-based fluorescence imaging has led to the widespread adoption of laser injury models to study hemostasis and thrombosis in mice. In all animal models of hemostasis and thrombosis, detailing the nature of experimentally induced vascular injury is paramount in enabling appropriate interpretation of experimental results. A careful appraisal of the literature shows that direct laser-induced injury can result in variable degrees of vascular damage. This review will compare and contrast models of laser injury utilized in the field, with an emphasis on the mechanism and extent of injury, the use of laser injury in different vascular beds and the molecular mechanisms regulating the response to injury. All of these topics will be discussed in the context of how distinct applications of laser injury models may be viewed as representing thrombosis and/or hemostasis.
Topics: Animals; Disease Models, Animal; Endothelial Cells; Femoral Artery; Hemostasis; Humans; Intravital Microscopy; Laser Therapy; Mice; Platelet Activation; Saphenous Vein; Thrombosis; Thromboxane A2; Vascular System Injuries
PubMed: 32297542
DOI: 10.1080/09537104.2020.1748589