Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway.
Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway.
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DOI：
10.7150/ijbs.16430
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发表时间：
2016
影响因子：
9.2
通讯作者：
Hsu JH
中科院分区：
文献类型：
--
作者：
Wu JR;Yeh JL;Liou SF;Dai ZK;Wu BN;Hsu JH
动脉导管未闭（PDA）可导致新生儿发病和死亡。以平滑肌细胞（SMC）增殖和迁移为特征的血管重构是出生后DA关闭的重要过程。Notch信号是血管重构的重要介质，但其在DA中的作用尚不清楚。我们研究了Notch信号抑制剂γ-分泌酶抑制剂DAPT对血管紧张素II（Ang II）诱导的DASMCs增殖和迁移的影响及其机制。用Ang Ⅱ诱导DASMCs的增殖和迁移，并与DAPT预处理相比较。此外，还对细胞周期进程、Ca 2+内流、活性氧（ROS）产生、MAPK和Akt信号转导、Notch受体及其靶基因通路等潜在的机制进行了研究。DAPT抑制Ang Ⅱ诱导的DASMCs增殖和迁移，并呈剂量依赖性。DAPT还可使细胞周期阻滞在G 0/G1期，并减轻Ang II引起的钙超载和ROS产生。此外，DAPT抑制Notch 3受体胞内结构域的核转位，其下游基因包括HES 1、HES 2和HES 5的表达降低。最后，Ang II激活的ERK 1/2、JNK和Akt也被DAPT抵消。总之，DAPT抑制Ang II诱导的DASMCs增殖和迁移。这些作用可能是通过Notch 3-HES 1/2/5途径减少钙内流、减少ROS产生以及下调ERK 1/2、JNK和Akt介导的。因此，Notch信号通路在DA重塑中起作用，并可能为PDA的治疗干预提供靶向途径。
Patent ductus arteriosus (PDA) can cause morbidity and mortality in neonates. Vascular remodeling, characterized by proliferation and migration of smooth muscle cells (SMCs), is an essential process for postnatal DA closure. Notch signaling is an important mediator of vascular remodelling but its role in DA is unkonwn. We investigated the effects and underlying mechanisms of γ-secretase inhibitor DAPT, a Notch signaling inhibitor on angiotensin II (Ang II)-induced proliferation and migration of DASMCs. Proliferation and migration of DASMCs cultured from neonatal Wistar rats were induced by Ang II, with or without DAPT pre-treatment. In addition, potential underlying mechanisms including cell cycle progression, Ca2+ influx, reactive oxygen species (ROS) production, signal transduction of MAPK and Akt, and Notch receptor with its target gene pathway were examined. We found that DAPT inhibited Ang II-induced DASMCs proliferation and migration dose dependently. DAPT also arrested the cell cycle progression in the G0/G1-phase, and attenuated calcium overload and ROS production caused by Ang II. Moreover, DAPT inhibited nuclear translocation of Notch3 receptor intracellular domain, with decreased expression of its down-stream genes including HES1, HES2 and HES5. Finally, Ang II-activated ERK1/2, JNK and Akt were also counteracted by DAPT. In conclusion, DAPT inhibits Ang II-induced DASMCs proliferation and migration. These effects are potentially mediated by decreased calcium influx, reduced ROS production, and down-regulation of ERK1/2, JNK and Akt, through the Notch3-HES1/2/5 pathway. Therefore, Notch signaling has a role in DA remodeling and may provide a target pathway for therapeutic intervention of PDA.