title: Imbalanced synthesis of cyclooxygenase-derived thromboxane A2 and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome.
abstract: OBJECTIVE
  Thoracic aortic dissection is a life-threatening complication of Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1. We have demonstrated that nitric oxide-mediated endothelial-dependent relaxation is impaired in the thoracic aorta in Marfan syndrome. In the present study, we determined whether the cyclooxygenase (COX)-pathway is involved in the compromised aortic vasomotor function.
  
  
  METHODS
  Thoracic aortae from mice at 3, 6 and 9 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), 'Marfan', n=35), were compared with those from age-matched controls (n=35).
  
  
  RESULTS
  Isometric force measurement revealed that preincubation with indomethacin, a non-specific COX inhibitor, but not valeryl salicylate, a specific COX-1 inhibitor, improved the phenylephrine-induced contractions (at 6 months, EC(50) and E(max) were increased 4.5-fold and by 45%, respectively) in Marfan aortae. Sensitivity to acetylcholine-induced relaxation was improved 10-fold. Blockade of the thromboxane-endoperoxide receptor by SQ-29548 did not affect phenylephrine-mediated contractions in Marfan aortae, although they did respond to the thromboxane analogue, U46619. From 6 months on, phenylephrine-induced secretion of prostacyclin and thromboxane A(2) in Marfan aortae was 200% and 40%, respectively, of those in controls. Reduced COX-1 expression was detected in Marfan aortae at 3 and 9 months, whilst COX-2 expression was increased from 3 months on.
  
  
  CONCLUSIONS
  The compromised vasomotor function in Marfan thoracic aortae is associated with an imbalanced synthesis of thromboxane A(2) and prostacyclin resulting from the differential protein expression of COX-1 and COX-2.
authors.affiliation: Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. achung@mrl.ubc.ca
authors.forename: A W Y
authors.initials: AW
authors.lastname: Chung
authors.forename: H H C
authors.initials: HH
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: van Breemen
mesh_terms: D000367:Age Factors; D000483:Alleles; D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology*; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000096:biosynthesis*; D000071838:Fibrillin-1; D000071837:Fibrillins; D005786:Gene Expression Regulation; D006579:Heterozygote; D007537:Isometric Contraction; D008382:Marfan Syndrome / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009154:Mutation; D010656:Phenylephrine; D013928:Thromboxane A2 / Q000096:biosynthesis*; D054392:Adipokines
chemical_list: D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D010656:Phenylephrine; D013928:Thromboxane A2; C000605724:Fbn1 protein, mouse; D054392:Adipokines