SLC44A2 - A novel therapeutic target for venous thrombosis?

Published on Jul 1, 2020in Journal of Thrombosis and Haemostasis4.157
· DOI :10.1111/JTH.14834
Adela Constantinescu-Bercu2
Estimated H-index: 2
(Imperial College London),
Isabelle I. Salles-Crawley6
Estimated H-index: 6
(Imperial College London),
James T. B. Crawley30
Estimated H-index: 30
(Imperial College London)
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Abstract
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References19
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#1Adela Constantinescu-Bercu (Imperial College London)H-Index: 2
#2Luigi Grassi (University of Cambridge)H-Index: 60
Last. James T. B. Crawley (Imperial College London)H-Index: 30
view all 6 authors...
Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Iba-dependent platelet 'priming' induces integrin aIIbb3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet aIIbb3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extrace...
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#1Julia Tilburg (LUMC: Leiden University Medical Center)H-Index: 3
#2Daniëlle M. Coenen (UM: Maastricht University)H-Index: 5
Last. Grace M. Thomas (AMU: Aix-Marseille University)H-Index: 8
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BACKGROUND: Genome wide association studies (GWAS) identified SLC44A2 as a novel susceptibility gene for venous thrombosis (VT) and previous work established that SLC44A2 contributed to clot formation upon vascular injury. OBJECTIVE: To further investigate the role of SLC44A2 in VT by utilizing SLC44A2 deficient mice (Slc44a2(-/-) ) in two representative disease models. METHODS: Mice were included in a hypercoagulability model driven by siRNA-mediated hepatic gene silencing of anticoagulants Ser...
10 CitationsSource
#1Dollapak Apipongrat (Thammasat University)H-Index: 1
Last. Oytip Nathalang (Thammasat University)H-Index: 12
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#1Julia Tilburg (LUMC: Leiden University Medical Center)H-Index: 3
#2Reheman Adili (UM: University of Michigan)H-Index: 12
Last. Michael Holinstat (UM: University of Michigan)H-Index: 34
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Abstract Introduction Recent genome wide association studies (GWAS) identified a novel susceptibility locus for thrombosis, harbouring the SLC44A2 gene which encodes the Solute Carrier Family 44 Member 2 protein (SLC44A2). Thus far, SLC44A2 has not been studied in the context of thrombosis, and may be a unique contributor to thrombotic disease. Here we utilize mice lacking SLC44A2 ( Slc44a2 −/− ) to evaluate a possible role of SLC44A2 in hemostasis. Methods Slc44a2 −/− mice were evaluated in key...
14 CitationsSource
#1Thankam S. Nair (UM: University of Michigan)H-Index: 15
#2Pavan K. Kommareddi (UM: University of Michigan)H-Index: 7
Last. Thomas E. Carey (UM: University of Michigan)H-Index: 80
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Abstract SLC44A2 was discovered as the target of an antibody that causes hearing loss. Knockout mice develop age related hearing loss, loss of sensory cells and spiral ganglion neurons. SLC44A2 has polymorphic sites implicated in human disease. Transfusion related acute lung injury (TRALI) is linked to rs2288904 and genome wide association studies link rs2288904 and rs9797861 to venous thromboembolism (VTE), coronary artery disease and stroke. Here we report linkage disequilibrium of rs2288904 w...
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#1Frits R. Rosendaal (LUMC: Leiden University Medical Center)H-Index: 136
Venous thrombosis which mainly manifests as deep vein thrombosis of the leg or pulmonary embolism occurs in 1 per 1000 per year. It occurs due to interacting genetic, environmental and behavioral risk factors. The strongest risk factors are certain types of surgery and malignancies. Over the last decade many new risk factors for venous thrombosis have been identified. Venous thrombosis has a high recurrence rate, of around 5 % per year. Whereas clinically it would be most important to identify p...
40 CitationsSource
#1David A. HindsH-Index: 71
#2Alfonso Buil (University of Geneva)H-Index: 34
Last. Maria Sabater-Lleal (KI: Karolinska Institutet)H-Index: 26
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Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism ...
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#1Noel C. ChanH-Index: 17
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Last. Jeffrey I. Weitz (Monash University, Clayton campus)H-Index: 1
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The direct oral anticoagulants (DOACs) represent a major advance in oral anticoagulant therapy and have replaced the vitamin K antagonists as the preferred treatment for many indications. By simplifying long-term anticoagulant therapy and improving its safety, the DOACs have the potential to reduce the global burden of thrombosis. Postmarketing studies suggest that the favorable results achieved with DOACs in the randomized controlled trials can be readily translated into practice, but highlight...
67 CitationsSource
#1Aaron M. Wendelboe (University of Oklahoma Health Sciences Center)H-Index: 20
#2Gary E. Raskob (University of Oklahoma Health Sciences Center)H-Index: 89
Thromboembolic conditions were estimated to account for 1 in 4 deaths worldwide in 2010 and are the leading cause of mortality. Thromboembolic conditions are divided into arterial and venous thrombotic conditions. Ischemic heart disease and ischemic stroke comprise the major arterial thromboses and deep-vein thrombosis and pulmonary embolism comprise venous thromboembolism. Atrial fibrillation is a major risk factor for stroke and systemic arterial thromboembolism. Estimates of the global burden...
258 CitationsSource
#1Pavan K. Kommareddi (UM: University of Michigan)H-Index: 7
#2Thankam S. Nair (UM: University of Michigan)H-Index: 15
Last. Thomas E. Carey (UM: University of Michigan)H-Index: 80
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SLC44A2 (solute carrier 44a2), also known as CTL2 (choline transporter-like protein 2), is expressed in many supporting cell types in the cochlea and is implicated in hair cell survival and antibody-induced hearing loss. In mice with the mixed C57BL/6-129 background, homozygous deletion of Slc44a2 exons 3–10 (Slc44a2 Δ/Δ) resulted in high-frequency hearing loss and hair cell death. To reduce effects associated with age-related hearing loss (ARHL) in these strains, mice carrying the Slc44a2 Δ all...
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Abstract The membrane phospholipids phosphatidylcholine and phosphatidylethanolamine (PE) are synthesized de novo by the CDP-choline and CDP-ethanolamine (Kennedy) pathway, in which the extracellular substrates choline and ethanolamine are transported into the cell, phosphorylated, and coupled with diacylglycerol to form the final phospholipid product. While multiple transport systems have been established for choline, ethanolamine transport is poorly characterized, and there is no single protei...
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#1Adrian Taylor (U of G: University of Guelph)H-Index: 4
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Abstract We examined a novel function of mammalian Choline-Transporter-Like proteins CTL1/SLC44A1 and CTL2/SLC44A2 in ethanolamine transport. We established two distinct ethanolamine transport systems of a high affinity (K1 = 55.6 - 66.5 μM), mediated by CTL1, and of a low affinity (K2 = 275 - 299 μM), mediated by CTL2. Both types of transport are Na+-independent and mediated in a pH dependent manner, as expected for ethanolamine/H+ antiporters. Primary human fibroblasts with separate frameshift...
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#1Adela Constantinescu-Bercu (Imperial College London)H-Index: 2
#2Luigi Grassi (University of Cambridge)H-Index: 60
Last. James T. B. Crawley (Imperial College London)H-Index: 30
view all 6 authors...
Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Iba-dependent platelet 'priming' induces integrin aIIbb3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet aIIbb3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extrace...
22 CitationsSource