In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 120, No. 6 ( 2009-08-11), p. 526-532
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-β might be mirrored in circulating TGF-β concentrations. Methods and Results— Serum obtained from MFS mutant mice ( Fbn1 C1039G /+ ) 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 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-β1 concentrations compared with age-matched Fbn1 C1039G /+ 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-β1 levels and aortic root diameters in Fbn1 C1039G /+ 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.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/CIRCULATIONAHA.108.841981
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2009
detail.hit.zdb_id:
1466401-X
