Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia.
Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia.
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DOI：
10.1016/j.bbamcr.2010.09.002
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Wang G;Zhang Z;Xu Z;Yin H;Bai L;Ma Z;Decoster MA;Qian G;Wu G
Hedgehog信号通路在血管新生和血管重塑中起着重要作用。然而，这一途径在肺血管平滑肌细胞增殖中的作用尚不清楚。在本研究中，我们已经证明了刺猬途径的主要成分，包括音刺猬（SHH），patched1（PTCH 1），smoothened（SMO），GLI和缺氧诱导因子1（HIF 1）在人肺动脉平滑肌细胞（HPASMCs）中表达。缺氧可显著增强SHH和HIF 1的表达，促进GLI 1向细胞核转位，促进HPASMCs增殖。此外，通过与纯化的重组人SHH或与purmorphamine和SAG（两种Smo激动剂）孵育直接激活SHH通路也增强了HPASMCs的增殖。重要的是，用抗SHH和抗HIF 1抗体或环巴胺（一种特异性SMO抑制剂）处理，显著抑制由缺氧和SHH通路激活诱导的HPASMCs中GLI 1的核转位和细胞增殖。此外，环巴胺处理增加缺氧HPASMCs的凋亡。这些数据首次有力地证明了SHH信号在缺氧条件下HPASMC生长的调节中起着至关重要的作用。
The hedgehog signal pathway plays a crucial role in the angiogenesis and vascular remodeling. However, the function of this pathway in the pulmonary vascular smooth cell proliferation in response to hypoxia remains unknown. In this study, we have demonstrated that the main components of the hedgehog pathway, including sonic hedgehog (SHH), patched1 (PTCH1), smoothened (SMO), GLI and hypoxia-inducible factor 1 (HIF1) are expressed in the human pulmonary arterial smooth muscle cells (HPASMCs). Interestingly, hypoxia significantly enhanced the expression of SHH and HIF1, facilitated the translocation of GLI1 into the nuclei, and promoted the proliferation of HPASMCs. Furthermore, direct activation of the SHH pathway through incubation with the purified recombinant human SHH or with purmorphamine and SAG, two Smo agonists, also enhanced the proliferation of HPASMCs. Importantly, the treatment with anti-SHH and anti-HIF1 antibodies or cyclopamine, a specific SMO inhibitor, markedly inhibited the nuclear translocation of GLI1 and cell proliferation in the HPASMCs induced by hypoxia and activation of the SHH pathway. Moreover, the treatment with cyclopamine increased apoptosis in the hypoxic HPASMCs. These data strongly demonstrate for the first time that the SHH signaling plays a crucial role in the regulation of HPASMC growth in response to hypoxia.
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