Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction.
Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction.
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DOI：
10.1007/s00109-014-1211-9
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发表时间：
2015-03
影响因子：
4.7
通讯作者：
Levinson, Howard
中科院分区：
文献类型：
--
作者：
Ehanire, Tosan;Ren, Licheng;Bond, Jennifer;Medina, Manuel;Li, George;Bashirov, Latif;Chen, Lei;Kokosis, George;Ibrahim, Mohamed;Selim, Angelica;Blobe, Gerard C.;Levinson, Howard
肥厚性疤痕收缩（HSc）是由肌成纤维细胞传播的肉芽组织收缩以及成纤维细胞的迁移和收缩引起的。确定促进迁移和收缩性的兴奋剂是缓解 HSc 的关键。血管紧张素II（AngII）促进心脏、肝脏和肺成纤维细胞的迁移和收缩；因此，我们研究了 AngII 在 HSc 中的机制。对人类疤痕和未受伤的真皮进行 AngII 受体 AT1 受体和 AT2 受体的免疫染色，并使用蛋白质印迹分析 AT1 受体的表达。使用 AT1 受体、AT2 受体、p38、JNK、MEK 和 ALK5 拮抗作用进行 AngII 刺激下成纤维细胞收缩和迁移的体外测定。在分别用 AngII ± 洛沙坦、ALK5 和 JNK 抑制剂 SB-431542 和 SP-600125 处理的 AT1 受体 KO 和 WT 小鼠上产生切除伤口。通过免疫组织化学对肉芽组织收缩进行量化并分析伤口。 AT1 受体的表达在疤痕中增加，但在未受伤的组织中没有增加。 AngII 通过 AT1 受体诱导成纤维细胞收缩和迁移。 ALK5 和 JNK 会抑制细胞迁移，但 p38 或 MEK 阻断不会抑制细胞迁移。体内实验确定，缺乏 AT1 受体和化学 AT1 受体拮抗作用会减弱肉芽组织收缩，而 AngII 会刺激伤口收缩。 ALK5 抑制会减弱 AngII 肉芽组织收缩，但 JNK 不会减弱。 AngII，通过 AT1 受体和下游经典 TGFβ 信号通路促进肉芽组织收缩； ALK5。进一步了解 HSc 作为一种整合信号传导机制的发病机制可以改善我们建立有效治疗干预措施的方法。
Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility are key to mitigating HSc. AngiotensinII (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors AT1-receptor and AT2-receptor, and analyzed for AT1-receptor expression using western blot. In-vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1-receptor, AT2-receptor, p38, JNK, MEK, and ALK5 antagonism. Excisional wounds were created on AT1-receptor KO and WT mice treated with AngII ± Losartan, and ALK5 and JNK inhibitors SB-431542 and SP-600125 respectively. Granulation tissue contraction was quantified and wounds analyzed by immunohistochemistry. AT1-receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1-receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In-vivo experiments determined that absence of AT1-receptor and chemical AT1-receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII, promotes granulation tissue contraction through AT1-receptor and downstream canonical TGFβ signaling pathway; ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions.
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影响因子：
13.8
作者：
Morihara, K;Takai, S;Kishimoto, S
通讯作者：
Kishimoto, S
影响因子：
82.9
作者：
Cohn, Ronald D.;van Erp, Christel;Dietz, Harry C.
通讯作者：
Dietz, Harry C.
影响因子：
6
作者：
Takeda, H;Katagata, Y;Kondo, S
通讯作者：
Kondo, S
DOI：
10.1038/nrm2786
发表时间：
2009-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.8
作者：
Li, Li;Fan, Dong;Wu, Li-Ling
通讯作者：
Wu, Li-Ling