title: Circulating transforming growth factor-beta in Marfan syndrome.
abstract: BACKGROUND
  Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-beta (TGF-beta). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-beta activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-beta might be mirrored in circulating TGF-beta concentrations.
  
  
  RESULTS
  Serum obtained from MFS mutant mice (Fbn1(C1039G/+)) treated with losartan was analyzed for circulating TGF-beta1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-beta1 concentrations increased with age and were elevated in older untreated Fbn1(C1039G/+) mice compared with wild-type mice (P=0.01; n=16; mean+/-SEM, 115+/-8 ng/mL versus n=17; mean+/-SEM, 92+/-4 ng/mL). Losartan-treated Fbn1(C1039G/+) mice had lower total TGF-beta1 concentrations compared with age-matched Fbn1(C1039G/+) mice treated with placebo (P=0.01; n=18; 90+/-5 ng/mL), and circulating total TGF-beta1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-beta1 levels and aortic root diameters in Fbn1(C1039G/+) and wild-type mice (P=0.002). In humans, circulating total TGF-beta1 concentrations were elevated in patients with MFS compared with control individuals (P<0.0001; n=53; 15+/-1.7 ng/mL versus n=74; 2.5+/-0.4 ng/mL). MFS patients treated with losartan (n=55) or beta-blocker (n=80) showed significantly lower total TGF-beta1 concentrations compared with untreated MFS patients (P< or =0.05).
  
  
  CONCLUSIONS
  Circulating TGF-beta1 concentrations are elevated in MFS and decrease after administration of losartan, beta-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.
authors.affiliation: 602 Mason F. Lord Bldg, Center Tower, Johns Hopkins University, Baltimore, MD 21239, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Matt
authors.forename: Florian
authors.initials: F
authors.lastname: Schoenhoff
authors.forename: Jennifer
authors.initials: J
authors.lastname: Habashi
authors.forename: Tammy
authors.initials: T
authors.lastname: Holm
authors.forename: Christel
authors.initials: C
authors.lastname: Van Erp
authors.forename: David
authors.initials: D
authors.lastname: Loch
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Griswold
authors.forename: Qin
authors.initials: Q
authors.lastname: Fu
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging; D015415:Biomarkers / Q000097:blood*; D004452:Echocardiography; D005260:Female; D006579:Heterozygote; D006801:Humans; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008382:Marfan Syndrome / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D011379:Prognosis; D053773:Transforming Growth Factor beta1 / Q000097:blood*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D053773:Transforming Growth Factor beta1; D019808:Losartan