Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice.
Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice.
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异常的机械感应和Cofilin激活促进了小鼠升主动脉瘤的进展。
DOI：
10.1126/scisignal.aab3141
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发表时间：
2015-10-20
影响因子：
7.3
通讯作者：
Yanagisawa H
中科院分区：
文献类型：
--
作者：
Yamashiro Y;Papke CL;Kim J;Ringuette LJ;Zhang QJ;Liu ZP;Mirzaei H;Wagenseil JE;Davis EC;Yanagisawa H
平滑肌细胞（SMC）和细胞外基质（ECM）在主动脉壁中密切相关。平滑肌细胞特异性缺失Fbln 4基因（编码血管ECM组分fibulin-4）的Fbln 4SMKO小鼠发生血管紧张素转换酶（ACE）丰度增加的升主动脉瘤;在生命的第一个月内抑制血管紧张素II信号传导可预防动脉瘤的发生。我们使用出生后第1天（P）至P30小鼠的Fbln 4SMKO动脉瘤的比较蛋白质组学分析来鉴定参与动脉瘤起始和扩张的关键分子。在P14，肌动蛋白解聚因子cofilin被去磷酸化，从而激活，并在P7，弹弓-1磷酸酶（SSH 1），cofilin的激活剂，丰度增加，导致肌动蛋白细胞骨架重塑。此外，通过P7，生物力学变化和不发达的弹性层-SMC连接是明显的，早期生长反应-1（Egr 1），一种刺激ACE表达的机械敏感性转录因子的丰度增加，这是在ACE丰度和cofilin激活增加之前。出生后在P7的SMC中Fbln 4的缺失阻止了cofilin激活和动脉瘤形成，这表明这些过程需要破坏弹性层-SMC连接。磷脂酰肌醇3-激酶（PI 3 K）参与血管紧张素II介导的SSH 1激活，从P7至P30给予PI 3 K抑制剂可降低SSH 1丰度并预防动脉瘤。这些结果表明，动脉瘤的形成是由于平滑肌细胞的异常机械感应引起的弹性层-平滑肌细胞连接的损失和增加的SSH 1和cofilin活性，这可能是治疗升主动脉瘤的潜在治疗靶点。
Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4SMKO mice with a smooth muscle cell-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4SMKO aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 phosphatase (SSH1), an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident and the abundance of early growth response-1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinsitide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1 and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.
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DOI：
10.1073/pnas.1208141109
发表时间：
2012-09-18
影响因子：
11.1
作者：
Beck, Henning;Flynn, Kevin;Knoell, Bernd
通讯作者：
Knoell, Bernd
影响因子：
2
作者：
Dasouki, Majed;Markova, Dessislava;Chu, Mon-Li
通讯作者：
Chu, Mon-Li
影响因子：
21.3
作者：
Gohla, A;Birkenfeld, J;Bokoch, GM
通讯作者：
Bokoch, GM
影响因子：
9.8
作者：
Guo, Dong-Chuan;Regalado, Ellen;Milewicz, Dianna M.
通讯作者：
Milewicz, Dianna M.
DOI：
10.1073/pnas.0908268106
发表时间：
2009-11-10
影响因子：
11.1
作者：
Horiguchi, Masahito;Inoue, Tadashi;Nakamura, Tomoyuki
通讯作者：
Nakamura, Tomoyuki