From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, PR China (X.M., Y.S., Y.Z.); Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study and School of Medicine, Nanjing University, Nanjing, PR China (M.Z.); and Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing, PR China (J.D.).
Circ Res. 2016 Feb 5;118(3):388-99. doi: 10.1161/CIRCRESAHA.115.308040. Epub 2015 Dec 23.
Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-β (TGF-β) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-β signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown.
To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms.
Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-β receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-β in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs.
The findings reveal that Smad4-dependent TGF-β signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-β signaling loss-of-function mutations.
主动脉瘤是一种危及生命的心血管疾病，其发生与夹层和破裂的易感性有关。遗传研究已经证明转化生长因子-β（TGF-β）途径参与了主动脉瘤的发生。Smad4 是经典 TGF-β信号通路的中心介质。然而，Smad4 在平滑肌细胞（SMC）中的确切作用导致主动脉瘤的发病机制在很大程度上尚不清楚。
确定平滑肌 Smad4 在主动脉瘤发病机制中的作用。
条件性基因敲除策略结合组织学和表达分析表明，SMC 中 Smad4 或 TGF-β 受体 II 缺乏会导致主动脉瘤的发生，并伴有组织蛋白酶 S 和基质金属蛋白酶-12 的上调，这两种酶是弹性蛋白降解所必需的。我们进一步证明了 TGF-β在主动脉 SMC 中对基质金属蛋白酶-12 的先前未知的下调，而 Smad4 的缺失则大大消除了这种下调。趋化性测定和药物治疗表明，Smad4 缺陷的 SMC 通过过度产生趋化因子直接引发主动脉壁炎症，从而招募巨噬细胞。单核细胞/巨噬细胞耗竭或阻断选择性趋化因子轴在很大程度上消除了 Smad4 缺陷的 SMC 引起的主动脉瘤的进展。
这些发现表明 Smad4 依赖性 TGF-β信号在 SMC 中可防止主动脉瘤的形成和夹层。这些数据还表明，对于新型治疗策略具有重要意义，可以限制由于 TGF-β信号功能丧失突变导致的动脉瘤进展。
