Matt Peter, Schoenhoff Florian, Habashi Jennifer, Holm Tammy, Van Erp Christel, Loch David, Carlson Olga D, Griswold Benjamin F, Fu Qin, De Backer Julie, Loeys Bart, Huso David L, McDonnell Nazli B, Van Eyk Jennifer E, Dietz Harry C
602 Mason F. Lord Bldg, Center Tower, Johns Hopkins University, Baltimore, MD 21239, USA.
Circulation. 2009 Aug 11;120(6):526-32. doi: 10.1161/CIRCULATIONAHA.108.841981. Epub 2009 Jul 27.
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.
马凡综合征（MFS）由原纤蛋白-1基因的突变和转化生长因子-β（TGF-β）的失调引起。最近的证据表明，氯沙坦是一种能抑制TGF-β激活的1型血管紧张素II受体阻滞剂，可能是治疗MFS的有效药物。我们推测TGF-β的失调可能反映在循环中TGF-β的浓度上。
分析用氯沙坦治疗的MFS突变小鼠（Fbn1(C1039G/+)）的血清中循环TGF-β1的浓度，并与用安慰剂治疗的小鼠和野生型小鼠的浓度进行比较。通过超声心动图测量主动脉根部大小。在MFS患者和健康个体中验证了数据。在小鼠中，循环中总TGF-β1浓度随年龄增加而升高，与野生型小鼠相比，未治疗的老年Fbn1(C1039G/+)小鼠中该浓度升高（P=0.01；n=16；平均值±标准误，115±8 ng/mL对n=17；平均值±标准误，92±4 ng/mL）。与用安慰剂治疗的年龄匹配的Fbn1(C1039G/+)小鼠相比，用氯沙坦治疗的Fbn1(C1039G/+)小鼠的总TGF-β1浓度较低（P=0.01；n=18；90±5 ng/mL），且循环中总TGF-β1水平与年龄匹配的野生型小鼠无差异（P=0.8）。在Fbn1(C1039G/+)和野生型小鼠中，观察到循环中TGF-β1水平与主动脉根部直径之间存在相关性（P=0.002）。在人类中，与对照个体相比，MFS患者循环中总TGF-β1浓度升高（P<0.0001；n=53；15±1.7 ng/mL对n=74；2.5±0.4 ng/mL）。与未治疗的MFS患者相比，用氯沙坦治疗的MFS患者（n=55）或用β受体阻滞剂治疗的MFS患者（n=80）的总TGF-β1浓度显著降低（P≤0.05）。
MFS患者循环中TGF-β1浓度升高，在给予氯沙坦、β受体阻滞剂治疗或两者联合治疗后降低，因此可能作为MFS的预后和治疗标志物。
