Circulating transforming growth factor-β in marfan syndrome

Peter Matt, Florian Schoenhoff, Jennifer Habashi, Tammy Holm, Christel Van Erp, David Loch, Olga D. Carlson, Benjamin F. Griswold, Qin Fu, Julie De Backer, Bart Loeys, David L. Huso, Nazli B. McDonnell, Jennifer E. Van Eyk, Harry C. Dietz

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-β (TGF-β). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-β activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-βmight be mirrored in circulating TGF-βconcentrations. Methods and Results-Serum obtained from MFS mutant mice (Fbn1C1039G/+) treated with losartan was analyzed for circulating TGF-β1 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-β1 concentrations increased with age and were elevated in older untreated Fbn1C1039G/+ 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 Fbn C1039G/+ mice had lower total TGF-β1 concentrations compared with age-matched Fbn1C1039G/+ mice treated with placebo (P=0.01; n=18; 90±5 ng/mL), and circulating total TGF-β1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF--1 levels and aortic root diameters in Fbn1C1039G/+and wild-type mice (P=0.002). In humans, circulating total TGF-β1 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 β-blocker (n=80) showed significantly lower total TGF-β1 concentrations compared with untreated MFS patients (P≤0.05). Conclusions-Circulating TGF-β1 concentrations are elevated in MFS and decrease after administration of losartan, β-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.

Original languageEnglish (US)
Pages (from-to)526-532
Number of pages7
JournalCirculation
Volume120
Issue number6
DOIs
StatePublished - Aug 11 2009

Keywords

  • Aneurysm
  • Biomarkers
  • Losartan
  • Marfan syndrome
  • TGF-beta

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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