Selective inhibitors of COX-2 increase the risk of myocardial infarction and athero-thrombotic events, but the mechanisms are not fully understood1,2. To assess the role of COX-2 in arterial thrombosis, a well-studied, chemically-induced model of arterial injury was applied to COX-2KO and data were compared with those obtained in wild-type (WT) mice. We found that thrombus formation in response to ferric chloride injury of the carotid arteries was significantly increased in COX-2KO than WT mice (Fig1). Figure 1: Kinetic of thrombus formation induced in response to ferric chloride injury of the carotid arteries in WT and COX-2KO mice. To understand the mechanisms responsible for the increase in thrombus formation, we first investigated the role of platelets in our experimental model. COX-2KO platelets showed enhanced response to collagen and ADP ex vivo in terms of aggregation together with increased ability to produce thromboxane compared with WT platelets. In this condition, COX-1 and thromboxane synthase protein levels were similar in both animal groups. However, using cross-transfusion experiments, we excluded that COX-2KO platelets were the responsible for the increased arterial thrombus formation in COX-2KO mice. Importantly, we found that the activity of tissue factor (TF) as an initiator of blood coagulation was elevated in concentrated microparticles derived from plasma as well as in leukocytes and in the carotid arteries of COX-2KO mice. Increased levels of TF mRNA correlated with reduced levels of prostacyclin synthase mRNA and decreased prostacyclin production in the arterial wall of COX-2KO mice. In addition, treatment with CAY10441, an antagonist of prostacyclin receptor (IP), increased TF activity in the carotid arteries of WT mice. Conversely, carbacyclin, a stable IP agonist, reduced TF activity in the carotid arteries of COX-2KO mice. These findings reveal for the first time that the propensity to thrombosis observed in association with COX-2 inhibition is consequent to the impairment in the generation of prostacyclin, which in turn results in increased TF expression and activity. References [1]D. Bishop-Bailey, J.A. Mitchell, T.D. Warner. COX-2 in Cardiovascular Disease. Arterioscler Thromb Vasc Biol, 26, 956-958, 2006. [2]S.D. Solomon, J.J.V. McMurray, M.A. Pfeffer, J.Wittes, R.Fowler, P.Finn, W.F.Anderson, A. Zauber, E. Hawk and Monica Bertagnolli. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention. N Engl J Med, 352, 1071-1080,2005

Prostacyclin reduction results in tissue factor (TF) upregulation and predisposes cyclooxygenase-2 knockout (COX-2KO) mice to thrombosis / S. Gianellini, S.S. Barbieri, P. Amadio, E. Zacchi, L.R. Howe, B.B. Weksler, L. Mussoni, E. Tremoli. ((Intervento presentato al 1. convegno Next step: la giovane ricerca avanza tenutosi a Milano nel 2010.

Prostacyclin reduction results in tissue factor (TF) upregulation and predisposes cyclooxygenase-2 knockout (COX-2KO) mice to thrombosis

S. Gianellini;S.S. Barbieri;P. Amadio;E. Zacchi;L. Mussoni;E. Tremoli
2010-07-01

Abstract

Selective inhibitors of COX-2 increase the risk of myocardial infarction and athero-thrombotic events, but the mechanisms are not fully understood1,2. To assess the role of COX-2 in arterial thrombosis, a well-studied, chemically-induced model of arterial injury was applied to COX-2KO and data were compared with those obtained in wild-type (WT) mice. We found that thrombus formation in response to ferric chloride injury of the carotid arteries was significantly increased in COX-2KO than WT mice (Fig1). Figure 1: Kinetic of thrombus formation induced in response to ferric chloride injury of the carotid arteries in WT and COX-2KO mice. To understand the mechanisms responsible for the increase in thrombus formation, we first investigated the role of platelets in our experimental model. COX-2KO platelets showed enhanced response to collagen and ADP ex vivo in terms of aggregation together with increased ability to produce thromboxane compared with WT platelets. In this condition, COX-1 and thromboxane synthase protein levels were similar in both animal groups. However, using cross-transfusion experiments, we excluded that COX-2KO platelets were the responsible for the increased arterial thrombus formation in COX-2KO mice. Importantly, we found that the activity of tissue factor (TF) as an initiator of blood coagulation was elevated in concentrated microparticles derived from plasma as well as in leukocytes and in the carotid arteries of COX-2KO mice. Increased levels of TF mRNA correlated with reduced levels of prostacyclin synthase mRNA and decreased prostacyclin production in the arterial wall of COX-2KO mice. In addition, treatment with CAY10441, an antagonist of prostacyclin receptor (IP), increased TF activity in the carotid arteries of WT mice. Conversely, carbacyclin, a stable IP agonist, reduced TF activity in the carotid arteries of COX-2KO mice. These findings reveal for the first time that the propensity to thrombosis observed in association with COX-2 inhibition is consequent to the impairment in the generation of prostacyclin, which in turn results in increased TF expression and activity. References [1]D. Bishop-Bailey, J.A. Mitchell, T.D. Warner. COX-2 in Cardiovascular Disease. Arterioscler Thromb Vasc Biol, 26, 956-958, 2006. [2]S.D. Solomon, J.J.V. McMurray, M.A. Pfeffer, J.Wittes, R.Fowler, P.Finn, W.F.Anderson, A. Zauber, E. Hawk and Monica Bertagnolli. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention. N Engl J Med, 352, 1071-1080,2005
carotid artery thrombosis ; thromboplastin ; prostaglandins ; knockout mice ; cyclooxygenase 2
Settore BIO/14 - Farmacologia
Centro di Ricerche Farmacologiche per lo Studio e la Prevenzione delle Malattie Cardiovascolari CRF
Prostacyclin reduction results in tissue factor (TF) upregulation and predisposes cyclooxygenase-2 knockout (COX-2KO) mice to thrombosis / S. Gianellini, S.S. Barbieri, P. Amadio, E. Zacchi, L.R. Howe, B.B. Weksler, L. Mussoni, E. Tremoli. ((Intervento presentato al 1. convegno Next step: la giovane ricerca avanza tenutosi a Milano nel 2010.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/165246
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