Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.
Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.
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DOI：
10.1371/journal.pone.0051514
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Qiao L;Xie L;Shi K;Zhou T;Hua Y;Liu H
肺动脉高压（PH）是一种缺乏有效治疗的致死性疾病。Notch信号通路在血管新生和血管重塑中起着重要作用。然而，其在PH血管重塑中的作用尚未得到很好的研究。在本研究中，我们使用缺氧诱导的大鼠PH模型，检测了Notch及其下游因子的表达。然后，我们使用血管条培养系统和Notch信号抑制剂γ-分泌酶抑制剂DAPT来确定Notch信号在血管重构中的作用及其潜在的治疗价值。我们的结果表明，Notch 1-4在肺组织中检测到不同水平的不同类型的细胞，如肺动脉、支气管和肺泡的平滑肌细胞和内皮细胞。此外，肺动脉Notch 1、Notch 3、Notch 4受体及下游因子HERP 1的mRNA表达在PH诱导后均增加，并在1-2周达到高峰。培养8 d后，缺氧处理大鼠血管壁厚度增加，DAPT可使其厚度减少约30%，同时凋亡因子caspase-3和Bax表达水平显著增加，血管平滑肌细胞（VSMC）表型由合成型向收缩型转变。总之，本研究提示Notch信号通路在PH肺血管重构中起重要作用，靶向Notch信号通路可能成为PH治疗的新途径。
Pulmonary hypertension (PH) is a fatal disease that lacks an effective therapy. Notch signaling pathway plays a crucial role in the angiogenesis and vascular remodeling. However, its roles in vascular remodeling in PH have not been well studied. In the current study, using hypoxia-induced PH model in rat, we examined the expression of Notch and its downstream factors. Then, we used vessel strip culture system and γ-secretase inhibitor DAPT, a Notch signaling inhibitor to determine the effect of Notch signaling in vascular remodeling and its potential therapeutic value. Our results indicated that Notch 1–4 were detected in the lung tissue with variable levels in different cell types such as smooth muscle cells and endothelial cells of pulmonary artery, bronchia, and alveoli. In addition, following the PH induction, all of Notch1, Notch3, Notch4 receptor, and downstream factor, HERP1 in pulmonary arteries, mRNA expressions were increased with a peak at 1–2 weeks. Furthermore, the vessel wall thickness from rats with hypoxia treatment increased after cultured for 8 days, which could be decreased approximately 30% by DAPT, accompanied with significant increase of expression level of apoptotic factors (caspase-3 and Bax) and transformation of vascular smooth muscle cell (VSMC) phenotype from synthetic towards contractile. In conclusion, the current study suggested Notch pathway plays an important role in pulmonary vascular remodeling in PH and targeting Notch signaling pathway could be a valuable approach to design new therapy for PH.
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影响因子：
37.8
作者：
Ii M;Takeshita K;Ibusuki K;Luedemann C;Wecker A;Eaton E;Thorne T;Asahara T;Liao JK;Losordo DW
通讯作者：
Losordo DW
影响因子：
11.8
作者：
Corada M;Nyqvist D;Orsenigo F;Caprini A;Giampietro C;Taketo MM;Iruela-Arispe ML;Adams RH;Dejana E
通讯作者：
Dejana E
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
Notch 和 TGF-β 信号通路之间的串扰由 Notch 胞内结构域与 Smad3 的相互作用介导。
影响因子：
7.8
作者：
Blokzijl, A;Dahlqvist, C;Reissmann, E;Falk, A;Moliner, A;Lendahl, U;Ibáñez, CF
通讯作者：
Ibáñez, CF
影响因子：
3.7
作者：
Dong X;Wang YS;Dou GR;Hou HY;Shi YY;Zhang R;Ma K;Wu L;Yao LB;Cai Y;Zhang J
通讯作者：
Zhang J