我们试图确定与二尖瓣 (BAV) 和单尖瓣 (UAV) 主动脉瓣相关的动脉瘤与正常主动脉瓣相比，转化生长因子-β (TGFß) 信号传导是否存在差异。升主动脉瘤常与 BAV 和 UAV 有关。这些机制尚未明确定义，但据报道与转化生长因子-β TGFß 血管病（即 Marfan、Loeys-Dietz 综合征）有相似之处。术中从具有 TAV（N = 10ND，10D）、BAV（N = 7ND，8D）或 UAV（N = 7ND，8D）的个体收集非扩张（ND）和动脉瘤（D）升主动脉组织。通过免疫测定和组织学分析评估 TGFß 信号和主动脉重塑。与 TAV 相比，BAV/UAV-ND 主动脉中的 TGFß1 增加（P = 0.02 和 0.04，分别）。有趣的是，TGFß1 在 TAV 中随着扩张而增加 ( P = 0.03)，在 BAV/UAV 中减少 ( P = 0.001)。在 TAV 中，SMAD2 和 SMAD3 磷酸化（pSMAD2、pSMAD3）随着扩张（所有P = 0.04）和 TGFß1 浓度（P = 0.04 和 0.03）而增加。对于 BAV/UAV，未观察到 TGFß1 与 pSMAD2 或 pSMAD3 之间的关系（所有P > 0.05）。pSMAD3 随着 BAV/UAV 主动脉扩张而增加 ( P = 0.01)，而未观察到与 pSMAD2 的关系 ( P = 0.56)。在所有组中，弹性蛋白断裂随着扩张而增加（所有P < 0.05)。在 TAV 中，弹性蛋白降解与 TGFß1、pSMAD2 和 pSMAD3 相关（所有P < 0.05），而在 BAV 和 UAV 主动脉中，弹性蛋白降解仅与 pSMAD3 相关（P = 0.0007）。通过 SMAD2/SMAD3 的 TGFß 信号传导有助于 TAV 中的主动脉重塑，而 TGFß 非依赖性 SMAD3 激活可能是 BAV/UAV 主动脉中动脉瘤形成的基础。因此，应进一步研究 SMAD3 作为一般抗升主动脉扩张的治疗靶点，特别是在 BAV/UAV 患者中。
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SMAD3 contributes to ascending aortic dilatation independent of transforming growth factor-beta in bicuspid and unicuspid aortic valve disease
We sought to determine whether there are differences in transforming growth factor-beta (TGFß) signaling in aneurysms associated with bicuspid (BAV) and unicuspid (UAV) aortic valves versus normal aortic valves. Ascending aortic aneurysms are frequently associated with BAV and UAV. The mechanisms are not yet clearly defined, but similarities to transforming growth factor-beta TGFß vasculopathies (i.e. Marfan, Loeys-Dietz syndromes) are reported. Non-dilated (ND) and aneurysmal (D) ascending aortic tissue was collected intra-operatively from individuals with a TAV (N = 10ND, 10D), BAV (N = 7ND, 8D) or UAV (N = 7ND, 8D). TGFß signaling and aortic remodeling were assessed through immuno-assays and histological analyses. TGFß1 was increased in BAV/UAV-ND aortas versus TAV (P = 0.02 and 0.04, respectively). Interestingly, TGFß1 increased with dilatation in TAV (P = 0.03) and decreased in BAV/UAV (P = 0.001). In TAV, SMAD2 and SMAD3 phosphorylation (pSMAD2, pSMAD3) increased with dilatation (all P = 0.04) and with TGFß1 concentration (P = 0.04 and 0.03). No relationship between TGFß1 and pSMAD2 or pSMAD3 was observed for BAV/UAV (all P > 0.05). pSMAD3 increased with dilatation in BAV/UAV aortas (P = 0.01), whereas no relationship with pSMAD2 was observed (P = 0.56). Elastin breaks increased with dilatation in all groups (all P < 0.05). In TAV, elastin degradation correlated with TGFß1, pSMAD2 and pSMAD3 (all P < 0.05), whereas in BAV and UAV aortas, elastin degradation correlated only with pSMAD3 (P = 0.0007). TGFß signaling through SMAD2/SMAD3 contributes to aortic remodeling in TAV, whereas TGFß-independent activation of SMAD3 may underlie aneurysm formation in BAV/UAV aortas. Therefore, SMAD3 should be further investigated as a therapeutic target against ascending aortic dilatation in general, and particularly in BAV/UAV patients.
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