Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1
Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1
复制标题
内皮素 1 激活肺动脉平滑肌细胞缺氧诱导因子 1
DOI：
10.1152/ajplung.00081.2012
复制
发表时间：
2013-04-01
影响因子：
4.9
通讯作者：
Shimoda, Larissa A.
中科院分区：
文献类型：
--
作者：
Pisarcik, Sarah;Maylor, Julie;Shimoda, Larissa A.
Pisarcik S，Maylor J，Lu W，Yun X，Undem C，西尔维斯特JT，Semenza GL，Shimoda LA.内皮素-1对肺动脉平滑肌细胞缺氧诱导因子-1的激活作用。Am J Physiol Lung Cell Mol Physiol 304：L549-L561，2013。首次发表于2013年2月15日; doi：10.1152/ajplung.00081.2012.-缺氧诱导因子-1（hypoxia-inducible factor-1，HIF-1）是一种重要的细胞缺氧反应因子。HIF-1在缺氧性肺动脉高压的发病机制中起着重要作用。在某些条件下，HIF-1可能利用前馈机制来放大其活性。由于缺氧增加了肺中内皮素-1（ET-1）的水平，我们推测，在中度，长期缺氧ET-1可能有助于肺动脉平滑肌细胞（PASMCs）的HIF-1信号。原代培养的大鼠PASMCs用ET-1处理或暴露于中度，长期缺氧（4%O-2 60小时）。缺氧细胞和ET-1处理的细胞中氧敏感性HIF-1 α亚基的水平和HIF靶基因的表达均增加。缺氧和ET-1也增加HIF-1 α mRNA表达，降低脯氨酰羟化酶2（PHD 2）的mRNA和蛋白表达，PHD 2是负责靶向HIF-1 α进行O-2依赖性降解的蛋白质。ET-1受体A亚型拮抗剂BQ-123可阻断中度、长期缺氧诱导的HIF-1 α。ET-1的作用是通过增加细胞内钙，产生活性氧和ERK 1/2激活介导的。ET-1和中度缺氧均不能诱导主动脉平滑肌细胞表达HIF-1 α或HIF靶基因。这些结果表明，ET-1通过上调HIF-1 α合成和下调PHD 2介导的降解诱导PASMC特异性HIF-1 α水平升高，从而在中度、长期缺氧期间放大PASMC中HIF-1 α的诱导。
Pisarcik S, Maylor J, Lu W, Yun X, Undem C, Sylvester JT, Semenza GL, Shimoda LA. Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1. Am J Physiol Lung Cell Mol Physiol 304: L549-L561, 2013. First published February 15, 2013; doi: 10.1152/ajplung.00081.2012.-Numerous cellular responses to hypoxia are mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 plays a central role in the pathogenesis of hypoxic pulmonary hypertension. Under certain conditions, HIF-1 may utilize feedforward mechanisms to amplify its activity. Since hypoxia increases endothelin-1 (ET-1) levels in the lung, we hypothesized that during moderate, prolonged hypoxia ET-1 might contribute to HIF-1 signaling in pulmonary arterial smooth muscle cells (PASMCs). Primary cultures of rat PASMCs were treated with ET-1 or exposed to moderate, prolonged hypoxia (4% O-2 for 60 h). Levels of the oxygen-sensitive HIF-1 alpha subunit and expression of HIF target genes were increased in both hypoxic cells and cells treated with ET-1. Both hypoxia and ET-1 also increased HIF-1 alpha mRNA expression and decreased mRNA and protein expression of prolyl hydroxylase 2 (PHD2), which is the protein responsible for targeting HIF-1 alpha for O-2-dependent degradation. The induction of HIF-1 alpha by moderate, prolonged hypoxia was blocked by BQ-123, an antagonist of ET-1 receptor subtype A. The effects of ET-1 were mediated by increased intracellular calcium, generation of reactive oxygen species, and ERK1/2 activation. Neither ET-1 nor moderate hypoxia induced the expression of HIF-1 alpha or HIF target genes in aortic smooth muscle cells. These results suggest that ET-1 induces a PASMC-specific increase in HIF-1 alpha levels by upregulation of HIF-1 alpha synthesis and downregulation of PHD2-mediated degradation, thereby amplifying the induction of HIF-1 alpha in PASMCs during moderate, prolonged hypoxia.