title: Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan syndrome.
abstract: OBJECTIVE
  Aortic complications account for the major mortality in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1. We hypothesized that MFS impaired endothelial function and nitric oxide (NO) production in the aorta.
  
  
  METHODS
  Mice (at 3, 6, 9 and 12 months of age) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), Marfan mice, n=75), the most common class of mutation in MFS, were compared with age-matched control littermates (n=75). Thoracic and abdominal aortas from the two groups were studied.
  
  
  RESULTS
  Isometric force measurements revealed that relaxation to ACh (but not to sodium nitroprusside) was diminished in the phenylephrine-precontracted Marfan thoracic aorta at 6 months of age (pEC(50)=6.12+/-0.22; maximal response, E(max)=52.7+/-6.8%; control: pEC(50)=7.34+/-0.19; E(max)=84.8+/-2.2%). At one year, both inhibition of NO production with N(omega)-nitro-L-arginine methyl ester, or denudation of endothelium increased the phenylephrine-stimulated contraction in the control thoracic aorta by 35%, but had no effect in the Marfan aorta, indicating a loss of basal NO production in the Marfan vessel. From 6 months, a reduced phosphorylation of endothelial NOS (eNOS)(Ser1177) and Akt(Thr308) detected by Western blotting was observed in the Marfan thoracic aorta, which was accompanied by decreased levels of cGMP. Expressions of Akt and eNOS in the abdominal aorta were not different between the two groups.
  
  
  CONCLUSIONS
  MFS impairs endothelial function and signaling of NO production in the thoracic aorta, suggesting the importance of NO in the age-related progression of thoracic aortic manifestations.
authors.affiliation: Child and Family Research Institute and Departments of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada. achung@mrl.ubc.ca
authors.forename: A W Y
authors.initials: AW
authors.lastname: Chung
authors.forename: K
authors.initials: K
authors.lastname: Au Yeung
authors.forename: S F
authors.initials: SF
authors.lastname: Cortes
authors.forename: G G S
authors.initials: GG
authors.lastname: Sandor
authors.forename: D P
authors.initials: DP
authors.lastname: Judge
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
authors.forename: C
authors.initials: C
authors.lastname: van Breemen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071838:Fibrillin-1; D000071837:Fibrillins; D008382:Marfan Syndrome / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054392:Adipokines
chemical_list: D000109:Acetylcholine; D002118:Calcium; D006152:Cyclic GMP; D004791:Enzyme Inhibitors; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D014665:Vasodilator Agents; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C496315:Nos3 protein, mouse