Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice

Summary

Deep-vein thrombosis (DVT) is a common condition that often leads to pulmonary thromboembolism (VTE) and death. The role of prostaglandin-endoperoxide synthase (PTGS)2 in arterial thrombosis has been well established, whereas its impact in venous thrombosis remains unclear. Here, we showed that PTGS2 deletion predisposes to venous thrombosis as suggested by greater clot firmness and clot elasticity, by higher plasma levels of functional fibrinogen, factor VIII and PAI-1 activity, and proved by bigger thrombi detected after inferior vena cava ligation (IVCL) compared to WT mice. PTGS2^-/- thrombi have greater fibrin content, higher number of F4/80⁺, TF⁺ and ANXA2⁺ cells, and lower S100A10⁺ cells. Remarkably, monocyte depletion reduced thrombus size in mutant mice, suggesting an important role of PTGS2^-/- monocytes in this experimental setting. Interestingly, PTGS2 deletion reduced membrane ANXA2, and total S100A10, promoted assembly of ANXA2/p50NF-kB complex and its nuclear accumulation, and induced TF in peritoneal macrophages, whereas ANXA2 silencing decreased dramatically TF. Finally, Carbaprostacyclin treatment prevented venous thrombus formation induced by IVCL in mutant mice, reduced the ANXA2 binding to p50NF-kB subunit and its nuclear trafficking, and decreased TF in PTGS2^-/- macrophages. PTGS2 deletion, changing the natural distribution of ANXA2 in monocytes/macro-phages, increases TF expression and activity predisposing to venous thrombosis. Interestingly, Carbaprostacyclin treatment, inhibiting nuclear ANXA2 trafficking, controls monocyte TF activity and prevents DVT occurrence. Our data are of help in elucidating the mechanisms by which PTGS2 inhibition increases DVT risk, and suggest a new role for ANXA2 in venous thrombosis.

Supplementary Material to this manuscript is available online at www.thrombosis-online.com.

Keywords

Prostaglandin-endoperoxide synthase-2 - prostacyclin - annexin-A2 - tissue factor - venous thrombosis

• References

• 1 Byers 3rd JM. Rudolf Virchow--father of cellular pathology. Am J Clin Pathol 1989; 92: S2-8.
• 2 Lisman T, de Groot PG, Meijers JC. et al. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105: 1102-1105.
• 3 Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol 2004; 24: 1015-1022.
• 4 Hedhli N, Falcone DJ, Huang B. et al. The annexin A2/S100A10 system in health and disease: emerging paradigms. J Biomed Biotechnol 2012; 2012; 406273.
• 5 Canas F, Simonin L, Couturaud F. et al. Annexin A2 autoantibodies in thrombosis and autoimmune diseases. Thromb Res 2015; 135: 226-230.
• 6 Jenkins PV, Rawley O, Smith OP. et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157: 653-663.
• 7 Ryan K, O'Donnell JS. Elevated plasma factor VIII levels in patients with venous thrombosis--constitutional risk factor or secondary epiphenomenon?. Thromb Res 2012; 129: 105-106.
• 8 Meltzer ME, Lisman T, de Groot PG. et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116: 113-121.
• 9 Mackman N. New insights into the mechanisms of venous thrombosis. J Clin Invest 2012; 122: 2331-2336.
• 10 Becattini C, Agnelli G, Prandoni P. et al. A prospective study on cardiovascular events after acute pulmonary embolism. Eur Heart J 2005; 26: 77-83.
• 11 Bova C, Marchiori A, Noto A. et al. Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism. A retrospective cohort study. Thromb Haemost 2006; 96: 132-136.
• 12 Sorensen HT, Horvath-Puho E, Pedersen L. et al. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370: 1773-1779.
• 13 Weksler BB. Prostanoids and NSAIDs in cardiovascular biology and disease. Curr Atheroscler Rep 2015; 17: 41.
• 14 Baigent C, Blackwell L, Collins R. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
• 15 Yu Y, Ricciotti E, Scalia R. et al. Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med 2012; 04: 132ra154.
• 16 Bresalier RS, Sandler RS, Quan H. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092-1102.
• 17 Barbieri SS, Amadio P, Gianellini S. et al. Cyclooxygenase-2-derived prostacyclin regulates arterial thrombus formation by suppressing tissue factor in a sirtuin-1-dependent-manner. Circulation 2012; 126: 1373-1384.
• 18 Kearney PM, Baigent C, Godwin J. et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of athero-thrombosis? Meta-analysis of randomised trials. Br Med J 2006; 332: 1302-1308.
• 19 Ray WA, Stein CM, Daugherty JR. et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360: 1071-1073.
• 20 Brighton TA, Eikelboom JW, Mann K. et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367: 1979-1987.
• 21 Sakata C, Kawasaki T, Kato Y. et al. ASP6537, a novel highly selective cyclo-oxygenase-1 inhibitor, exerts potent antithrombotic effect without „aspirin dilemma". Thromb Res 2013; 132: 56-62.
• 22 Simes J, Becattini C, Agnelli G. et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130: 1062-1071.
• 23 Tarantino E, Amadio P, Squellerio I. et al. Role of thromboxane-dependent platelet activation in venous thrombosis: Aspirin effects in mouse model. Pharmacol Res 2016; 107: 415-425.
• 24 Schmidt M, Christiansen CF, Horvath-Puho E. et al. Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism. J Thromb Haemost 2011; 09: 1326-1333.
• 25 Goy J, Paikin J, Crowther M. Rofecoxib does not appear to increase the risk of venous thromboembolism: a systematic review of the literature. Thromb Res 2014; 134: 997-1003.
• 26 Amadio P, Colombo GI, Tarantino E. et al. BDNFVa166met polymorphism: a potential bridge between depression and thrombosis. Eur Heart J 2017; 38: 1426-1435.
• 27 Aghourian MN, Lemarie CA, Blostein MD. In vivo monitoring of venous thrombosis in mice. J Thromb Haemost 2012; 10: 447-452.
• 28 McKenzie CG, Kim M, Singh TK. et al. Peripheral blood monocyte-derived chemokine blockade prevents murine transfusion-related acute lung injury (TRALI). Blood 2014; 123: 3496-3503.
• 29 Jonsson F, Mancardi DA, Kita Y. et al. Mouse and human neutrophils induce anaphylaxis. J Clin Invest 2011; 121: 1484-1496.
• 30 Barbieri SS, Petrucci G, Tarantino E. et al. Abnormal megakaryopoiesis and platelet function in cyclooxygenase-2-deficient mice. Thromb Haemost 2015; 114: 1218-1229.
• 31 Amadio P, Baldassarre D, Tarantino E. et al. Production of prostaglandin E2 induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells. FASEB J 2015; 29: 4001-4010.
• 32 Barbieri SS, Weksler BB. Tobacco smoke cooperates with interleukin-1beta to alter beta-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro in vivo. Faseb J 2007; 21: 1831-1843.
• 33 von Bruhl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
• 34 Sullivan VV, Hawley AE, Farris DM. et al. Decrease in fibrin content of venous thrombi in selectin-deficient mice. J Surg Res 2003; 109: 1-7.
• 35 Zhou H, Wang H, Li N. et al. Annexin A2 mediates anti-beta 2 GPI/beta 2 GPI-induced tissue factor expression on monocytes. Int J Mol Med 2009; 24: 557-562.
• 36 Leenen PJ, de Bruijn MF, Voerman JS. et al. Markers of mouse macrophage development detected by monoclonal antibodies. J Immunol Methods 1994; 174: 5-19.
• 37 McKnight AJ, Gordon S. Membrane molecules as differentiation antigens of murine macrophages. Adv Immunol 1998; 68: 271-314.
• 38 Kirchhofer D, Riederer MA, Baumgartner HR. Specific accumulation of circulating monocytes and polymorphonuclear leukocytes on platelet thrombi in a vascular injury model. Blood 1997; 89: 1270-1278.
• 39 Nosaka M, Ishida Y, Kimura A. et al. Absence of IFN-gamma accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice. J Clin Invest 2011; 121: 2911-2920.
• 40 Siefert SA, Chabasse C, Mukhopadhyay S. et al. Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice. J Thromb Haemost 2014; 12: 1706-1716.
• 41 Ramacciotti E, Hawley AE, Farris DM. et al. Leukocyte- and platelet-derived microparticles correlate with thrombus weight and tissue factor activity in an experimental mouse model of venous thrombosis. Thromb Haemost 2009; 101: 748-754.
• 42 Day SM, Reeve JL, Pedersen B. et al. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 2005; 105: 192-198.
• 43 Rezende SM, Lijfering WM, Rosendaal FR. et al. Hematologic variables and venous thrombosis: red cell distribution width and blood monocyte count are associated with an increased risk. Haematologica 2014; 99: 194-200.
• 44 Deora AB, Kreitzer G, Jacovina AT. et al. An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface. J Biol Chem 2004; 279: 43411-43418.
• 45 Flood EC, Hajjar KA. The annexin A2 system and vascular homeostasis. Vascul Pharmacol 2011; 54: 59-67.
• 46 Surette AP, Madureira PA, Phipps KD. et al. Regulation of fibrinolysis by S100A10 in vivo. Blood 2011; 118: 3172-3181.
• 47 Jung H, Kim JS, Kim WK. et al. Intracellular annexin A2 regulates NF-kappaB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer. Cell Death Dis 2015; 06: e1606.
• 48 Ahmetaj-Shala B, Kirkby NS, Knowles R. et al. Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs. Circulation 2015; 131: 633-642.
• 49 Iacoviello L, De Curtis A, D’Adamo MC. et al. Prostacyclin is required for t-PA release after venous occlusion. Am J Physiol 1994; 266: H429-434.
• 50 Lanham JG, Levin M, Brown Z. et al. Prostacyclin deficiency in a young woman with recurrent thrombosis. Br Med J 1986; 292: 435-436.