28 results on '"Van Kruchten R"'
Search Results
2. Signaling role of CD36 in platelet activation and thrombus formation on immobilized thrombospondin or oxidized low‐density lipoprotein
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NERGIZ‐UNAL, R., LAMERS, M.M.E., VAN KRUCHTEN, R., LUIKEN, J.J., COSEMANS, J.M.E.M., GLATZ, J.F.C., KUIJPERS, M.J.E., and HEEMSKERK, J.W.M.
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- 2011
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3. Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization
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COSEMANS, J.M.E.M., VAN KRUCHTEN, R., OLIESLAGERS, S., SCHURGERS, L.J., VERHEYEN, F.K., MUNNIX, I.C.A., WALTENBERGER, J., ANGELILLO‐SCHERRER, A., HOYLAERTS, M.F., CARMELIET, P., and HEEMSKERK, J.W.M.
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- 2010
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4. Advanced multi-parameter assessment of microspot thrombus formation: a systems biology approach: PA 3.02–2
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De Witt, S M, Lamers, M, Swieringa, F, Van Kruchten, R, Mastenbroek, T G, Coort, S, Cavill, R, Pugh, N, Farndale, R W, Clemetson, K J, Heemskerk, J WM, and Cosemans, J MEM
- Published
- 2013
5. Redundant functions of TRPC6 and Orai1 in murine platelets: PA 2.02–2
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Chen, W, Gupta, S, Thielmann, I, Gotru, S K, Van Kruchten, R, Dietrich, A, Heemskerk, J WM, Nieswandt, B, and Braun, A
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- 2013
6. The Scott syndrome protein anoctamin 6 (TMEM16F) regulates multiple cell death responses including membrane phospholipid scrambling in platelets: OC 11.3
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Mattheij, N, Braun, A, Van Kruchten, R, Cosemans, J MEM, Van Der Meijden, P EJ, Baaten, C, Ehlen, H WA, Schreiber, R, Vortkamp, A, Collins, P W, Bevers, E M, Ousingsawat, J, Kunzelmann, K, Nieswandt, B, and Heemskerk, J WM
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- 2013
7. Store-operated calcium entry as a potential target to suppress arterial thrombus formation: O-TH-019
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van Kruchten, R, Braun, A, Feijge, M AH, Schmidt, D E, Kraft, P, Stoll, G, Kuijpers, M JE, Bevers, E M, Nieswandt, B, and Heemskerk, J WM
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- 2011
8. Role of TMEM16F in agonist-induced but not apoptosis-induced phosphatidylserine exposure in scott platelets: O-TH-006
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van Kruchten, R, Wolfs, J LN, Feijge, M AH, Mattheij, N JA, Collins, P, Heemskerk, J WM, and Bevers, E M
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- 2011
9. Role of platelet Orai1 and STIM1 in GPVI-dependent and GPVI-independent thrombus formation and procoagulant activity: AS-TU-037
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Gilio, K, van Kruchten, R, Braun, A, Elvers, M, van der Meijden, P EJ, Feijge, M AH, Kuijpers, M JE, Stegner, D, Heemskerk, J WM, and Nieswandt, B
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- 2009
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10. P281 Combined clinical and biological response (concomitant CRP and faecal calprotectin reductions) in induction and maintenance from the phase 3 ustekinumab Crohn’s disease studies
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Colombel, J -F, primary, Gasink, C, additional, Oortwijn, A, additional, van Kruchten, R, additional, Sloan, S, additional, Laliman, V, additional, Rutgeerts, P, additional, Ghosh, S, additional, Sandborn, W, additional, Feagan, B, additional, and Sands, B, additional
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- 2018
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11. Platelet procoagulant acitivity: focus on calcium entry and phospholipid scrambling
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van Kruchten, R., van Kruchten, R., van Kruchten, R., and van Kruchten, R.
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- 2014
12. Leukocyte-derived microparticles in vascular homeostasis
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Angelillo-Scherrer Anne, Van Kruchten R, Olieslagers S, Schurgers L J, Verheyen F K, Munnix I C A, Waltenberger J, Angelillo-Scherrer A, Hoylaerts M F, Carmeliet P, and Heemskerk J W M
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Endothelium ,Physiology ,Angiogenesis ,030204 cardiovascular system & hematology ,Biology ,medicine.disease_cause ,Proinflammatory cytokine ,Neovascularization ,03 medical and health sciences ,0302 clinical medicine ,Cell-Derived Microparticles ,medicine ,Leukocytes ,Animals ,Homeostasis ,Humans ,Platelet activation ,Endothelial dysfunction ,030304 developmental biology ,0303 health sciences ,medicine.disease ,Vulnerable plaque ,3. Good health ,medicine.anatomical_structure ,Cardiovascular Diseases ,Hemostasis ,Immunology ,Disease Progression ,Blood Vessels ,medicine.symptom ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine - Abstract
Leukocyte-derived microparticles (LMPs) may originate from neutrophils, monocytes/macrophages, and lymphocytes. They express markers from their parental cells and harbor membrane and cytoplasmic proteins as well as bioactive lipids implicated in a variety of mechanisms, maintaining or disrupting vascular homeostasis. When they carry tissue factor or coagulation inhibitors, they participate in hemostasis and pathological thrombosis. Both proinflammatory and anti-inflammatory processes can be affected by LMPs, thus ensuring an appropriate inflammatory response. LMPs also play a dual role in the endothelium by either improving the endothelial function or inducing an endothelial dysfunction. LMPs are implicated in all stages of atherosclerosis. They circulate at a high level in the bloodstream of patients with high atherothrombotic risk, such as smokers, diabetics, and subjects with obstructive sleep apnea, where their prolonged contact with the vessel wall may contribute to its overall deterioration. Numbering microparticles, including LMPs, might be useful in predicting cardiovascular events. LMPs modify the endothelial function and promote the recruitment of inflammatory cells in the vascular wall, necessary processes for the progression of the atherosclerotic lesion. In addition, LMPs favor the neovascularization within the vulnerable plaque and, in the ruptured plaque, they take part in coagulation and platelet activation. Finally, LMPs participate in angiogenesis. They might represent a novel therapeutic tool to reset the angiogenic switch in pathologies with altered angiogenesis. Additional studies are needed to further investigate the role of LMPs in cardiovascular diseases. However, large-scale studies are currently difficult to set up because microparticle measurement still requires elaborate techniques which lack standardization.
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- 2012
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13. Signaling role of CD36 in platelet activation and thrombus formation on immobilized thrombospondin or oxidized low-density lipoprotein
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Nergiz-Unal, R., Nergiz-Unal, R., Lamers, M. M. E., Van Kruchten, R., Luiken, J. J., Cosemans, J. M. E. M., Glatz, J. F. C., Kuijpers, M. J. E., Heemskerk, J. W. M., Nergiz-Unal, R., Nergiz-Unal, R., Lamers, M. M. E., Van Kruchten, R., Luiken, J. J., Cosemans, J. M. E. M., Glatz, J. F. C., Kuijpers, M. J. E., and Heemskerk, J. W. M.
- Abstract
Background and Objective: Platelets abundantly express glycoprotein CD36 with thrombospondin-1 (TSP1) and oxidized low-density lipoprotein (oxLDL) as proposed ligands. How these agents promote platelet activation is still poorly understood. Methods and Results: Both TSP1 and oxLDL caused limited activation of platelets in suspension. However, immobilized TSP1 and oxLDL, but not LDL, strongly supported platelet adhesion and spreading with a major role of CD36. Platelet spreading was accompanied by potent Ca2+ rises, and resulted in exposure of P-selectin and integrin activation, all in a CD36-dependent manner with additional contributions of alpha(IIb)beta(3) and ADP receptor stimulation. Signaling responses via CD36 involved activation of the protein tyrosine kinase Syk. In whole blood perfusion, co-coating of TSP1 or oxLDL with collagen enhanced thrombus formation at high-shear flow conditions, with increased expression on platelets of activated alpha(IIb)beta(3), P-selectin and phosphatidylserine, again in a CD36-dependent way. Conclusions: Immobilized TSP1 and oxLDL activate platelets partly via CD36 through a Syk kinase-dependent Ca2+ signaling mechanism, which enhances collagen-dependent thrombus formation under flow. These findings provide novel insight into the role of CD36 in hemostasis.
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- 2011
14. Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization
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Cosemans, J. M. E. M., Cosemans, J. M. E. M., Van Kruchten, R., Olieslagers, S., Schurgers, L. J., Verheyen, F. K., Munnix, I. C. A., Waltenberger, J., Angelillo-Scherrer, Anne, Hoylaerts, Marc F., Carmeliet, P., Heemskerk, J. W. M., Cosemans, J. M. E. M., Cosemans, J. M. E. M., Van Kruchten, R., Olieslagers, S., Schurgers, L. J., Verheyen, F. K., Munnix, I. C. A., Waltenberger, J., Angelillo-Scherrer, Anne, Hoylaerts, Marc F., Carmeliet, P., and Heemskerk, J. W. M.
- Abstract
Background: Interaction of murine Gas6 with the platelet Gas6 receptors Tyro3, Axl and Mer (TAM) plays an important role in arterial thrombus formation. However, a role for Gas6 in human platelet activation has been questioned. Objective: To determine the role of Gas6 in human and murine platelet activation and thrombus formation. Methods and Results: Gas6 levels appeared to be 20-fold higher in human plasma than in platelets, suggesting a predominant role of plasma-derived Gas6. Human Gas6 synergizes with ADP-P2Y(12) by enhancing and prolonging the phosphorylation of Akt. Removal of Gas6 from plasma impaired ADP-induced platelet aggregation. Under flow conditions, absence of human Gas6 provoked gradual platelet disaggregation and integrin alpha(IIb)beta(3) inactivation. Recombinant human Gas6 reversed the effects of Gas6 removal. In mouse blood, deficiency in Gas6 or in one of the TAM receptors led to reduced thrombus formation and increased disaggregation, which was completely antagonized by external ADP. In contrast, collagen-induced platelet responses were unchanged by the absence of Gas6 in both human and mouse systems. Conclusions: The ADP-P2Y(12) and Gas6-TAM activation pathways synergize to achieve persistent alpha(IIb)beta(3) activation and platelet aggregation. We postulate a model of thrombus stabilization in which plasma Gas6, by signaling via the TAM receptors, extends and enhances the platelet-stabilizing effect of autocrine ADP, particularly when secretion becomes limited.
- Published
- 2010
15. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis
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Wouters, Kristiaan, Wouters, Kristiaan, van Gorp, P.J.J., Bieghs, V., Gijbels, M.J., Duimel, H., Lutjohann, D., Kerksiek, A., van Kruchten, R., Maeda, N., Staels, B., van Bilsen, M., Sverdlov, R., Hofker, M.H., Wouters, Kristiaan, Wouters, Kristiaan, van Gorp, P.J.J., Bieghs, V., Gijbels, M.J., Duimel, H., Lutjohann, D., Kerksiek, A., van Kruchten, R., Maeda, N., Staels, B., van Bilsen, M., Sverdlov, R., and Hofker, M.H.
- Abstract
Nonalcoholic steatohepatitis (NASH) involves liver lipid accumulation (steatosis) combined with hepatic inflammation. The transition towards hepatic inflammation represents a key step in pathogenesis, because it will set the stage for further liver damage, culminating in hepatic fibrosis, cirrhosis, and liver cancer. The actual risk factors that drive hepatic inflammation during the progression to NASH remain largely unknown. The role of steatosis and dietary cholesterol in the etiology of diet-induced NASH was investigated using hyperlipidemic mouse models fed a Western diet. Livers of male and female hyperlipidemic (low-density lipoprotein receptor-deficient [ldlr(-/-)] and apolipoprotein E2 knock-in [APOE2ki]) mouse models were compared with livers of normolipidemic wild-type (WT) C57BL/6J mice after short-term feeding with a high-fat diet with cholesterol (HFC) and without cholesterol. Whereas WT mice displayed only steatosis after a short-term HFC diet, female ldlr(-/-) and APOE2ki mice showed steatosis with severe inflammation characterized by infiltration of macrophages and increased nuclear factor kappaB (NF-kappaB) signaling. Remarkably, male ldlr(-/-) and APOE2ki mice developed severe hepatic inflammation in the absence of steatosis after 7 days on an HFC diet compared with WT animals. An HFC diet induced bloated, "foamy" Kupffer cells in male and female ldlr(-/-) and APOE2ki mice. Hepatic inflammation was found to be linked to increased plasma very low-density lipoprotein (VLDL) cholesterol levels. Omitting cholesterol from the HFC diet lowered plasma VLDL cholesterol and prevented the development of inflammation and hepatic foam cells. Conclusion: These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH. (HEPATOLOGY 2008;48:474-486.).
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- 2008
16. Calcium-activated and apoptotic phospholipid scrambling induced by Ano6 can occur independently of Ano6 ion currents
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Kmit, A, primary, van Kruchten, R, additional, Ousingsawat, J, additional, Mattheij, N J A, additional, Senden-Gijsbers, B, additional, Heemskerk, J W M, additional, Schreiber, R, additional, Bevers, E M, additional, and Kunzelmann, K, additional
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- 2013
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17. Platelet procoagulant acitivity: focus on calcium entry and phospholipid scrambling
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van Kruchten, R., primary
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18. Orai1‐induced store‐operated Ca2+entry enhances phospholipase activity and modulates canonical transient receptor potential channel 6 function in murine platelets
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Chen, W., Thielmann, I., Gupta, S., Subramanian, H., Stegner, D., van Kruchten, R., Dietrich, A., Gambaryan, S., Heemskerk, J.W.M., Hermanns, H.M., Nieswandt, B., and Braun, A.
- Abstract
Orai1, the major store‐operated Ca2+entry (SOCE) channel in platelets, is not only critical for enhancing diverse signaling pathways, but may also regulate receptor‐operated Ca2+entry (ROCE). Dynamic coupling of the Orai1 signalosome to canonical transient receptor potential channels (TRPCs) has been suggested as an essential step in the activation of SOCE and ROCE. However, the functional significance of the biochemical interaction between Orai and TRPC isoforms remains controversial.
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- 2014
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19. Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage.
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Mattheij NJ, Braun A, van Kruchten R, Castoldi E, Pircher J, Baaten CC, Wülling M, Kuijpers MJ, Köhler R, Poole AW, Schreiber R, Vortkamp A, Collins PW, Nieswandt B, Kunzelmann K, Cosemans JM, and Heemskerk JW
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- Animals, Anoctamin-1, Anoctamins, Blood Coagulation Disorders genetics, Blood Coagulation Disorders pathology, Blood Platelets pathology, Calcium metabolism, Cell Membrane genetics, Cell Membrane metabolism, Cell Membrane pathology, Chloride Channels genetics, Chloride Channels metabolism, Female, Humans, Intermediate-Conductance Calcium-Activated Potassium Channels genetics, Intermediate-Conductance Calcium-Activated Potassium Channels metabolism, Male, Mice, Mice, Knockout, Mutation, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Phospholipid Transfer Proteins genetics, Phospholipids genetics, Blood Coagulation Disorders metabolism, Blood Platelets metabolism, Phospholipid Transfer Proteins metabolism, Phospholipids metabolism, Proteolysis
- Abstract
Scott syndrome is a rare bleeding disorder, characterized by altered Ca(2+)-dependent platelet signaling with defective phosphatidylserine (PS) exposure and microparticle formation, and is linked to mutations in the ANO6 gene, encoding anoctamin (Ano)6. We investigated how the complex platelet phenotype of this syndrome is linked to defective expression of Anos or other ion channels. Mice were generated with heterozygous of homozygous deficiency in Ano6, Ano1, or Ca(2+)-dependent KCa3.1 Gardos channel. Platelets from these mice were extensively analyzed on molecular functions and compared with platelets from a patient with Scott syndrome. Deficiency in Ano1 or Gardos channel did not reduce platelet responses compared with control mice (P > 0.1). In 2 mouse strains, deficiency in Ano6 resulted in reduced viability with increased bleeding time to 28.6 min (control 6.4 min, P < 0.05). Platelets from the surviving Ano6-deficient mice resembled platelets from patients with Scott syndrome in: 1) normal collagen-induced aggregate formation (P > 0.05) with reduced PS exposure (-65 to 90%); 2) lowered Ca(2+)-dependent swelling (-80%) and membrane blebbing (-90%); 3) reduced calpain-dependent protein cleavage (-60%); and 4) moderately affected apoptosis-dependent PS exposure. In conclusion, mouse deficiency of Ano6 but not of other channels affects viability and phenocopies the complex changes in platelets from hemostatically impaired patients with Scott syndrome., (© FASEB.)
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- 2016
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20. Identification of platelet function defects by multi-parameter assessment of thrombus formation.
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de Witt SM, Swieringa F, Cavill R, Lamers MM, van Kruchten R, Mastenbroek T, Baaten C, Coort S, Pugh N, Schulz A, Scharrer I, Jurk K, Zieger B, Clemetson KJ, Farndale RW, Heemskerk JW, and Cosemans JM
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- Adult, Computational Biology, Female, Humans, Male, Middle Aged, Platelet Aggregation physiology, Young Adult, Biological Assay methods, Thrombosis diagnosis, Thrombosis metabolism
- Abstract
Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi-surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.
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- 2014
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21. Supporting roles of platelet thrombospondin-1 and CD36 in thrombus formation on collagen.
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Kuijpers MJ, de Witt S, Nergiz-Unal R, van Kruchten R, Korporaal SJ, Verhamme P, Febbraio M, Tjwa M, Voshol PJ, Hoylaerts MF, Cosemans JM, and Heemskerk JW
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- Animals, Mice, Mice, Inbred C57BL, Platelet Activation, Platelet Adhesiveness, Platelet Glycoprotein GPIIb-IIIa Complex physiology, CD36 Antigens physiology, Collagen metabolism, Thrombosis etiology, Thrombospondin 1 physiology
- Abstract
Objective: Platelets abundantly express the membrane receptor CD36 and store its ligand thrombospondin-1 (TSP1) in the α-granules. We investigated whether released TSP1 can support platelet adhesion and thrombus formation via interaction with CD36., Approach and Results: Mouse platelets deficient in CD36 showed reduced adhesion to TSP1 and subsequent phosphatidylserine expression. Deficiency in either CD36 or TSP1 resulted in markedly increased dissolution of thrombi formed on collagen, although thrombus buildup was unchanged. In mesenteric vessels in vivo, deficiency in CD36 prolonged the time to occlusion and enhanced embolization, which was in agreement with earlier observations in TSP1-deficient mice. Thrombi formed using wild-type blood stained positively for secreted TSP1. Releasate from wild-type but not from TSP1-deficient platelets enhanced platelet activation, phosphatidylserine expression, and thrombus formation on collagen. The enhancement was dependent on CD36 because it was without effect on thrombus formation by CD36-deficient platelets., Conclusions: These results demonstrate an anchoring role of platelet-released TSP1 via CD36 in platelet adhesion and collagen-dependent thrombus stabilization. Thus, the TSP1-CD36 tandem is another platelet ligand-receptor axis contributing to the maintenance of a stable thrombus., (© 2014 American Heart Association, Inc.)
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- 2014
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22. Dual mechanism of integrin αIIbβ3 closure in procoagulant platelets.
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Mattheij NJ, Gilio K, van Kruchten R, Jobe SM, Wieschhaus AJ, Chishti AH, Collins P, Heemskerk JW, and Cosemans JM
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- Animals, Anoctamins, Blood Platelets drug effects, Blood Platelets physiology, CD36 Antigens metabolism, Calcium Signaling, Calpain antagonists & inhibitors, Calpain metabolism, Cell Membrane metabolism, Crotalid Venoms pharmacology, Dipeptides pharmacology, Humans, Lectins, C-Type, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mitochondria metabolism, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Permeability Transition Pore, Phosphatidylserines metabolism, Phospholipid Transfer Proteins metabolism, Platelet Aggregation, Protein Structure, Quaternary, Proteolysis, Talin metabolism, Thrombin pharmacology, Thrombin physiology, src-Family Kinases metabolism, Blood Platelets metabolism, Platelet Glycoprotein GPIIb-IIIa Complex metabolism
- Abstract
Background: Inactivation of integrin αIIbβ3 reverses platelet aggregate formation upon coagulation., Results and Conclusion: Platelets from patient (Scott) and mouse (Capn1(-/-) and Ppif(-/-)) blood reveal a dual mechanism of αIIbβ3 inactivation: by calpain-2 cleavage of integrin-associated proteins and by cyclophilin D/TMEM16F-dependent phospholipid scrambling., Significance: These data provide novel insight into the switch mechanisms from aggregating to procoagulant platelets. Aggregation of platelets via activated integrin αIIbβ3 is a prerequisite for thrombus formation. Phosphatidylserine-exposing platelets with a key role in the coagulation process disconnect from a thrombus by integrin inactivation via an unknown mechanism. Here we show that αIIbβ3 inactivation in procoagulant platelets relies on a sustained high intracellular Ca(2+), stimulating intracellular cleavage of the β3 chain, talin, and Src kinase. Inhibition of calpain activity abolished protein cleavage, but only partly suppressed αIIbβ3 inactivation. Integrin αIIbβ3 inactivation was unchanged in platelets from Capn1(-/-) mice, suggesting a role of the calpain-2 isoform. Scott syndrome platelets, lacking the transmembrane protein TMEM16F and having low phosphatidylserine exposure, displayed reduced αIIbβ3 inactivation with the remaining activity fully dependent on calpain. In platelets from Ppif(-/-) mice, lacking mitochondrial permeability transition pore (mPTP) formation, agonist-induced phosphatidylserine exposure and αIIbβ3 inactivation were reduced. Treatment of human platelets with cyclosporin A gave a similar phenotype. Together, these data point to a dual mechanism of αIIbβ3 inactivation via calpain(-2) cleavage of integrin-associated proteins and via TMEM16F-dependent phospholipid scrambling with an assistant role of mPTP formation.
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- 2013
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23. Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation.
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van Kruchten R, Mattheij NJ, Saunders C, Feijge MA, Swieringa F, Wolfs JL, Collins PW, Heemskerk JW, and Bevers EM
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- Anoctamins, Blood Coagulation Disorders metabolism, Blood Platelets metabolism, Case-Control Studies, Caspases metabolism, Crotalid Venoms pharmacology, Cyclophilins metabolism, Flow Cytometry, Hemostatics pharmacology, Humans, Lectins, C-Type, Mitochondria drug effects, Mitochondria metabolism, Thrombin pharmacology, Apoptosis, Blood Coagulation Disorders pathology, Blood Platelets pathology, Calcium metabolism, Phosphatidylserines metabolism, Phospholipid Transfer Proteins metabolism, Platelet Activation
- Abstract
Scott syndrome, a bleeding disorder caused by defective phospholipid scrambling, has been associated with mutations in the TMEM16F gene. The role of TMEM16F in apoptosis- or agonist-induced phosphatidylserine (PS) exposure was studied in platelets from a Scott syndrome patient and control subjects. Whereas stimulation of control platelets with the BH3-mimetic ABT737 resulted in 2 distinct fractions with moderate and high PS exposure, the high PS-exposing fraction was markedly delayed in Scott platelets. High, but not moderate, PS exposure in platelets was suppressed by chelation of intracellular Ca(2+), whereas caspase inhibition completely abolished ABT737-induced PS exposure in both Scott and control platelets. On the other hand, high PS exposure induced by the Ca(2+)-mobilizing agonists convulxin/thrombin fully relied on mitochondrial depolarization and was virtually absent in Scott platelets. Finally, PS exposure induced by collagen/thrombin was partly affected in Scott platelets, and the residual PS positive fraction was insensitive to inhibition of caspases or mitochondrial depolarization. In conclusion, TMEM16F is not required for, but enhances, caspase-dependent PS exposure; convulxin-/thrombin-induced PS exposure is entirely dependent on TMEM16F, whereas collagen/thrombin-induced PS exposure results from 2 distinct pathways, one of which involves mitochondrial depolarization and is mediated by TMEM16F.
- Published
- 2013
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24. Antithrombotic potential of blockers of store-operated calcium channels in platelets.
- Author
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van Kruchten R, Braun A, Feijge MA, Kuijpers MJ, Rivera-Galdos R, Kraft P, Stoll G, Kleinschnitz C, Bevers EM, Nieswandt B, and Heemskerk JW
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- Animals, Boron Compounds pharmacology, Calcium metabolism, Calcium Channels physiology, Humans, Mice, Mice, Inbred C57BL, ORAI1 Protein, Platelet Activation drug effects, Blood Platelets drug effects, Calcium Channel Blockers pharmacology, Fibrinolytic Agents pharmacology
- Abstract
Objective: Platelet Orai1 channels mediate store-operated Ca(2+) entry (SOCE), which is required for procoagulant activity and arterial thrombus formation. Pharmacological blockage of these channels may provide a novel way of antithrombotic therapy. Therefore, the thromboprotective effect of SOCE blockers directed against platelet Orai1 is determined., Methods and Results: Candidate inhibitors were screened for their effects on SOCE in washed human platelets. Tested antagonists included the known compounds, SKF96365, 2-aminoethyl diphenylborate, and MRS1845 and the novel compounds, Synta66 and GSK-7975A. The potency of SOCE inhibition was in the order of Synta66>2-aminoethyl diphenylborate>GSK-7975A>SKF96365>MRS1845. The specificity of the first 3 compounds was verified with platelets from Orai1-deficient mice. Inhibitory activity on procoagulant activity and high-shear thrombus formation was assessed in plasma and whole blood. In the presence of plasma, all 3 compounds suppressed platelet responses and restrained thrombus formation under flow. Using a murine stroke model, arterial thrombus formation was provoked in vivo by transient middle cerebral artery occlusion. Postoperative administration of 2-aminoethyl diphenylborate markedly diminished brain infarct size., Conclusions: Plasma-soluble SOCE blockers such as 2-aminoethyl diphenylborate suppress platelet-dependent coagulation and thrombus formation. The platelet Orai1 channel is a novel target for preventing thrombotic events causing brain infarction.
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- 2012
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25. Measurement of whole blood thrombus formation using parallel-plate flow chambers - a practical guide.
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Van Kruchten R, Cosemans JM, and Heemskerk JW
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- Animals, Humans, Mice, Platelet Function Tests instrumentation, Platelet Function Tests methods, Rats, Blood Coagulation, Blood Platelets metabolism, Platelet Activation
- Abstract
Custom-made and commercial parallel-plate flow chambers are widely used for studies of platelet activation and thrombus formation in whole blood at defined shear rates. When used in a reproducible way, such flow chamber devices give valuable information on the thrombogenic potential of human, mouse, or rat blood. This article aims to provide a practical guide for the use of parallel-plate flow chambers in combination with routine microscopic imaging techniques. The following methodological aspects are addressed: preparation of surface coatings, calculation of blood flow and shear rate, control of pre-analytical variables, protocols for routine performing of flow chamber tests with non-coagulating or coagulating blood, and procedures for real-time and end-point analysis of thrombus formation. Frequently encountered experimental problems and artifacts are discussed, as well as possibilities for using flow chamber devices as a diagnostic tool to test antithrombotic medication.
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- 2012
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26. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis.
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Lievens D, Zernecke A, Seijkens T, Soehnlein O, Beckers L, Munnix IC, Wijnands E, Goossens P, van Kruchten R, Thevissen L, Boon L, Flavell RA, Noelle RJ, Gerdes N, Biessen EA, Daemen MJ, Heemskerk JW, Weber C, and Lutgens E
- Subjects
- Animals, Atherosclerosis complications, Atherosclerosis metabolism, Cell Communication, Cell Movement, Chemokine CCL2 metabolism, Disease Progression, Endothelial Cells metabolism, Endothelial Cells pathology, Homeostasis, Inflammation complications, Iron metabolism, Leukocytes metabolism, Leukocytes pathology, Macrophages metabolism, Macrophages pathology, Mice, Phenotype, T-Lymphocytes immunology, Thrombosis complications, Atherosclerosis pathology, Blood Platelets metabolism, CD40 Ligand metabolism, Inflammation metabolism, Inflammation pathology, Thrombosis metabolism, Thrombosis pathology
- Abstract
CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L-deficient (Cd40l(-/-)) platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l(-/-) platelets into Apoe(-/-) mice strongly decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wild-type platelets. Moreover, Cd40l(-/-) platelets failed to form proinflammatory platelet-leukocyte aggregates. Expression of CD40L on platelets was required for platelet-induced atherosclerosis as injection of Cd40l(-/-) platelets in contrast to Cd40l(+/+) platelets did not promote lesion formation. Remarkably, injection of Cd40l(+/+), but not Cd40l(-/-), platelets transiently decreased the amount of regulatory T cells (Tregs) in blood and spleen. Depletion of Tregs in mice injected with activated Cd40l(-/-) platelets abrogated the athero-protective effect, indicating that CD40L on platelets mediates the reduction of Tregs leading to accelerated atherosclerosis. We conclude that platelet CD40L plays a pivotal role in atherosclerosis, not only by affecting platelet-platelet interactions but especially by activating leukocytes, thereby increasing platelet-leukocyte and leukocyte-endothelium interactions.
- Published
- 2010
- Full Text
- View/download PDF
27. Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation.
- Author
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Gilio K, van Kruchten R, Braun A, Berna-Erro A, Feijge MA, Stegner D, van der Meijden PE, Kuijpers MJ, Varga-Szabo D, Heemskerk JW, and Nieswandt B
- Subjects
- Animals, Blood Platelets metabolism, Calcium chemistry, Calcium metabolism, Female, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, ORAI1 Protein, Stromal Interaction Molecule 1, Calcium Channels metabolism, Coagulants metabolism, Membrane Glycoproteins metabolism, Platelet Membrane Glycoproteins metabolism, Thrombin metabolism, Thrombosis metabolism
- Abstract
In platelets, STIM1 has been recognized as the key regulatory protein in store-operated Ca(2+) entry (SOCE) with Orai1 as principal Ca(2+) entry channel. Both proteins contribute to collagen-dependent arterial thrombosis in mice in vivo. It is unclear whether STIM2 is involved. A key platelet response relying on Ca(2+) entry is the surface exposure of phosphatidylserine (PS), which accomplishes platelet procoagulant activity. We studied this response in mouse platelets deficient in STIM1, STIM2, or Orai1. Upon high shear flow of blood over collagen, Stim1(-/-) and Orai1(-/-) platelets had greatly impaired glycoprotein (GP) VI-dependent Ca(2+) signals, and they were deficient in PS exposure and thrombus formation. In contrast, Stim2(-/-) platelets reacted normally. Upon blood flow in the presence of thrombin generation and coagulation, Ca(2+) signals of Stim1(-/-) and Orai1(-/-) platelets were partly reduced, whereas the PS exposure and formation of fibrin-rich thrombi were normalized. Washed Stim1(-/-) and Orai1(-/-) platelets were deficient in GPVI-induced PS exposure and prothrombinase activity, but not when thrombin was present as co-agonist. Markedly, SKF96365, a blocker of (receptor-operated) Ca(2+) entry, inhibited Ca(2+) and procoagulant responses even in Stim1(-/-) and Orai1(-/-) platelets. These data show for the first time that: (i) STIM1 and Orai1 jointly contribute to GPVI-induced SOCE, procoagulant activity, and thrombus formation; (ii) a compensating Ca(2+) entry pathway is effective in the additional presence of thrombin; (iii) platelets contain two mechanisms of Ca(2+) entry and PS exposure, only one relying on STIM1-Orai1 interaction.
- Published
- 2010
- Full Text
- View/download PDF
28. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis.
- Author
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Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lütjohann D, Kerksiek A, van Kruchten R, Maeda N, Staels B, van Bilsen M, Shiri-Sverdlov R, and Hofker MH
- Subjects
- Animals, Apolipoprotein E2 metabolism, Dietary Fats administration & dosage, Disease Models, Animal, Fatty Liver complications, Female, Foam Cells pathology, Gene Expression Profiling, Gene Transfer Techniques, Hepatitis metabolism, Hepatitis pathology, Hepatitis prevention & control, Hyperlipidemias blood, Hyperlipidemias metabolism, Hyperlipidemias pathology, Lipids blood, Lipoproteins, VLDL blood, Liver metabolism, Liver pathology, Macrophages pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B metabolism, Receptors, LDL deficiency, Signal Transduction, Cholesterol, Dietary, Hepatitis etiology, Hyperlipidemias complications
- Abstract
Unlabelled: Nonalcoholic steatohepatitis (NASH) involves liver lipid accumulation (steatosis) combined with hepatic inflammation. The transition towards hepatic inflammation represents a key step in pathogenesis, because it will set the stage for further liver damage, culminating in hepatic fibrosis, cirrhosis, and liver cancer. The actual risk factors that drive hepatic inflammation during the progression to NASH remain largely unknown. The role of steatosis and dietary cholesterol in the etiology of diet-induced NASH was investigated using hyperlipidemic mouse models fed a Western diet. Livers of male and female hyperlipidemic (low-density lipoprotein receptor-deficient [ldlr(-/-)] and apolipoprotein E2 knock-in [APOE2ki]) mouse models were compared with livers of normolipidemic wild-type (WT) C57BL/6J mice after short-term feeding with a high-fat diet with cholesterol (HFC) and without cholesterol. Whereas WT mice displayed only steatosis after a short-term HFC diet, female ldlr(-/-) and APOE2ki mice showed steatosis with severe inflammation characterized by infiltration of macrophages and increased nuclear factor kappaB (NF-kappaB) signaling. Remarkably, male ldlr(-/-) and APOE2ki mice developed severe hepatic inflammation in the absence of steatosis after 7 days on an HFC diet compared with WT animals. An HFC diet induced bloated, "foamy" Kupffer cells in male and female ldlr(-/-) and APOE2ki mice. Hepatic inflammation was found to be linked to increased plasma very low-density lipoprotein (VLDL) cholesterol levels. Omitting cholesterol from the HFC diet lowered plasma VLDL cholesterol and prevented the development of inflammation and hepatic foam cells., Conclusion: These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.
- Published
- 2008
- Full Text
- View/download PDF
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