血栓反应蛋白-1 在机械转导和鼠与人胸主动脉瘤发生发展中的作用。
Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans.
机构信息
From the Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (Y.Y., S.J.S., K.S., H.Y.).
Department of Cardiovascular Surgery (B.Q.T., C.T., H.S., M.O., Y.H.).
出版信息
Circ Res. 2018 Aug 31;123(6):660-672. doi: 10.1161/CIRCRESAHA.118.313105.
RATIONALE
Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated.
OBJECTIVE
The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy.
METHODS AND RESULTS
We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4; termed SMKO [SMC-specific knockout]), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in SMKO ascending aortas and in human thoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in ≈80% of DKO (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas, and mechanical testing showed that structural and material properties of DKO aortas were markedly improved.
CONCLUSIONS
Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.
背景
平滑肌细胞（SMCs）异常的机械感受能力，源于弹性蛋白-收缩单位的缺陷，被认为是导致胸主动脉瘤形成的原因；然而，其确切的分子机制尚未阐明。
目的
本研究旨在确定在动脉瘤形成过程中异常机械感受和生化信号转导过程中的关键介质，并为新的治疗策略奠定基础。
方法和结果
我们使用了一种升主动脉动脉瘤的小鼠模型（Fbln4；称为 SMKO [SMC 特异性敲除]），其中 Fbln4（纤连蛋白-4）的缺失导致弹性纤维-SMC 连接的丧失，从而破坏了弹性蛋白-收缩单位。在这种小鼠中，Egr1（早期生长反应 1）和血管紧张素转换酶的上调导致 Ang II（血管紧张素 II）信号的激活。在这里，我们表明细胞外基质蛋白 Thbs1（血小板反应蛋白-1）在 SMKO 升主动脉和人类胸主动脉瘤中高度上调。Thbs1 由机械拉伸和 SMC 中的 Ang II 诱导，Egr1 是必需的，而 Fbln4 的缺失使细胞对这些刺激更加敏感，并导致 Egr1 和 Thbs1 的表达增加。在 SMKO 小鼠中敲除 Thbs1 可防止约 80%的 DKO（SMKO；Thbs1 敲除）动物发生动脉瘤形成，并抑制 Ssh1（弹弓-1）和肌动蛋白丝去磷酸化，导致正常的肌动蛋白丝形成。此外，DKO 主动脉中的弹性纤维-SMC 连接得到恢复，力学测试表明 DKO 主动脉的结构和材料特性得到显著改善。
结论
Thbs1 是机械转导的关键组成部分，也是弹性纤维组织的调节剂。Thbs1 的适应性上调导致弹性蛋白-收缩单位的破坏和肌动蛋白细胞骨架重塑的失调，导致体内升主动脉瘤的发展。Thbs1 可能成为治疗胸主动脉瘤的潜在治疗靶点。
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