Circulating Transforming Growth Factor-β in Marfan Syndrome

• Published in: Circulation (New York, N.Y.) Vol. 120; no. 6; pp. 526 - 532
• Main Authors: MATT, Peter, SCHOENHOFF, Florian, LOEYS, Bart, HUSO, David L, MCDONNELL, Nazli B, VAN EYK, Jennifer E, DIETZ, Harry C, HABASHI, Jennifer, HOLM, Tammy, VAN ERP, Christel, LOCH, David, CARLSON, Olga D, GRISWOLD, Benjamin F, QIN FU, DE BACKER, Julie
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 11.08.2009
• Subjects: Adult; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Aorta - diagnostic imaging; Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Echocardiography; Female; Fundamental and applied biological sciences. Psychology; Heterozygote; Humans; Losartan - pharmacology; Male; Marfan Syndrome - blood; Marfan Syndrome - drug therapy; Marfan Syndrome - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Prognosis; Transforming Growth Factor beta1 - blood; Vertebrates: cardiovascular system; Imidazole derivatives; Connective tissue disease; Tetrazole derivatives; Skin disease; Elastic tissue disease; Transforming growth factor β; biomarkers; Peptide hormone; Aneurysm; Non peptide compound; Cardiovascular disease; Marfan syndrome; Genetic disease; Vascular disease; Octapeptide; Renin angiotensin system; TGF-beta; Biphenyl derivatives; Losartan; Systemic disease; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; Angiotensin II
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.108.841981

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. 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). 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.