title: Cyclooxygenase-2-derived prostacyclin regulates arterial thrombus formation by suppressing tissue factor in a sirtuin-1-dependent-manner.
abstract: BACKGROUND
  Selective inhibitors of cyclooxygenase (COX)-2 increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood.
  
  
  RESULTS
  We found that ferric chloride-induced arterial thrombus formation was significantly greater in COX-2 knockout compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor- and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-δ antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor-δ agonist completely reversed the thrombotic phenotype in COX-2 knockout mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity and promoted generation of occlusive thrombi in wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice.
  
  
  CONCLUSIONS
  Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-δ pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors.
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, 20138 Milano, Italy. silviabarbieri@yahoo.com
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Barbieri
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amadio
authors.forename: Sara
authors.initials: S
authors.lastname: Gianellini
authors.forename: Eva
authors.initials: E
authors.lastname: Tarantino
authors.forename: Elena
authors.initials: E
authors.lastname: Zacchi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.forename: Louise R
authors.initials: LR
authors.lastname: Howe
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.forename: Luciana
authors.initials: L
authors.lastname: Mussoni
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000453:epidemiology* / Q000378:metabolism*; D002712:Chlorides / Q000009:adverse effects; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D005290:Ferric Compounds / Q000009:adverse effects; D015994:Incidence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors; D044006:Receptors, Epoprostenol / Q000819:agonists / Q000037:antagonists & inhibitors; D012307:Risk Factors; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D047494:PPAR delta; D044006:Receptors, Epoprostenol; D013925:Thromboplastin; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C024555:ferric chloride