Circulating transforming growth factor-beta in Marfan syndrome.
Circulating transforming growth factor-beta in Marfan syndrome.
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DOI：
10.1161/circulationaha.108.841981
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发表时间：
2009-08-11
期刊：
影响因子：
37.8
通讯作者：
GenTAC Consortium
中科院分区：
文献类型：
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作者：
Matt P;Schoenhoff F;Habashi J;Holm T;Van Erp C;Loch D;Carlson OD;Griswold BF;Fu Q;De Backer J;Loeys B;Huso DL;McDonnell NB;Van Eyk JE;Dietz HC;GenTAC Consortium
马凡综合征 (MFS) 是由原纤维蛋白-1 基因突变和转化生长因子 β (TGFβ) 失调引起的。最近的证据表明，氯沙坦（一种 AT1 阻滞剂，可抑制 TGFβ 激活）可能是治疗 MFS 的有效方法。我们假设 TGFβ 的失调可能反映在循环 TGFβ 浓度中。对从用氯沙坦治疗的 MFS 突变小鼠 (Fbn1C1039G/+) 获得的血清进行循环 TGFβ1 浓度分析，并与安慰剂治疗和野生型小鼠的血清进行比较。通过超声心动图测量主动脉根部尺寸。数据在 MFS 患者和健康个体中得到验证。在小鼠中，循环总 TGFβ1 浓度随着年龄的增长而增加，并且与野生型小鼠相比，老年未治疗的 Fbn1C1039G/+ 小鼠的循环总 TGFβ1 浓度升高（P=0.01；n=16，平均值±SEM 115±8 ng/ml vs. n=17, 92±4 ng/ml）。与用安慰剂治疗的年龄匹配的 Fbn1C1039G/+ 小鼠相比，氯沙坦治疗的 Fbn1C1039G/+ 小鼠的总 TGFβ1 浓度较低（P=0.01；n=18, 90±5 ng/ml），并且循环总 TGFβ1 水平与年龄匹配的野生型小鼠没有区别（P=0.8）。在 Fbn1C1039G/+ 和野生型小鼠中观察到循环 TGFβ1 水平与主动脉根直径之间存在相关性 (P=0.002)。在人类中，与对照个体相比，MFS 患者的循环总 TGFβ1 浓度升高（P<0.0001；n=53, 15±1.7 ng/ml vs. n=74, 2.5±0.4 ng/ml）。与未经治疗的马凡氏患者相比，接受氯沙坦 (n=55) 或 β 受体阻滞剂 (n=80) 治疗的 MFS 患者的 TGFβ1 总浓度显着降低 (P≤0.05)。 MFS 中循环 TGFβ1 浓度升高，在给予氯沙坦和/或 β 受体阻滞剂治疗后降低，因此可能作为 MFS 的预后和治疗标志物。
Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor β (TGFβ). Recent evidence suggests that losartan, an AT1 blocker that blunts TGFβ activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGFβ might be mirrored in circulating TGFβ concentrations. Serum obtained from MFS mutant mice (Fbn1C1039G/+) treated with losartan was analyzed for circulating TGFβ1 concentrations, and compared to those from placebo treated and wild-type mice. Aortic root size was measured by echocardiography. Data was validated in patients with MFS and healthy individuals. In mice, circulating total TGFβ1 concentrations increased with age and were elevated in older untreated Fbn1C1039G/+ mice compared to wild-type mice (P=0.01; n=16, mean±SEM 115±8 ng/ml vs. n=17, 92±4 ng/ml). Losartan-treated Fbn1C1039G/+ mice had lower total TGFβ1 concentrations compared to age-matched Fbn1C1039G/+ mice treated with placebo (P=0.01; n=18, 90±5 ng/ml), and circulating total TGFβ1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGFβ1 levels and aortic root diameters in Fbn1C1039G/+ and wild-type mice (P=0.002). In humans, circulating total TGFβ1 concentrations were elevated in patients with MFS compared to control individuals (P<0.0001; n=53, 15±1.7 ng/ml vs. n=74, 2.5±0.4 ng/ml). MFS patients treated with losartan (n=55) or β-blocker (n=80) showed significantly lower total TGFβ1 concentrations compared to untreated Marfans (P≤0.05). Circulating TGFβ1 concentrations are elevated in MFS, decrease after administration of losartan and/or β-blocker therapy, and therefore might serve as prognostic and therapeutic marker in MFS.