HYPOXIA-INDUCED ALVEOLAR EPITHELIAL-MESENCHYMAL TRANSITION REQUIRES MITOCHONDRIAL ROS AND HYPOXIA-INDUCIBLE FACTOR 1. Export

@article{citeulike:6031333, abstract = {Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies suggest that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of alpha smooth muscle actin (alpha-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat and mouse AEC,suggesting that hypoxia induces EMT in AEC. Both severe and moderate hypoxia induce EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced EMT. Moreover, hypoxia-induced expression of alpha-SMA and vimentin was prevented in mitochondria-deficient rho(0) cells, which are incapable of ROS production during hypoxia. CoCl2 and DMOG, two compounds that stabilize HIF-alpha under normoxia, failed to induce alpha-SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1alpha did not induce alpha-SMA. However, loss of HIF-1alpha or HIF-2alpha abolished induction of alpha-SMA mRNA during hypoxia. Hypoxia increased the levels of transforming growth factor-beta1 (TGF-beta1) and pre-incubation of AEC with SB431542, an inhibitor of the TGF-beta1 type I receptor kinase, prevented the hypoxia-induced EMT, suggesting that the process was TGF-beta1 dependent. Furthermore, both ROS and HIF-alpha were necessary for hypoxia-induced TGF-beta1 upregulation. Accordingly, we provide evidence that hypoxia induces EMT of AEC through mitochondrial ROS, HIF and endogenous TGF-beta1 signaling. Key words: alveolar epithelial cells, pulmonary fibrosis, transforming growth factor beta 1.}, author = {Zhou, Guofei and Dada, Laura A. and Wu, Minghua and Kelly, Aileen and Trejo, Humberto and Zhou, Qiyuan and Varga, John and Sznajder, Jacob Iasha I.}, citeulike-article-id = {6031333}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajplung.00007.2009}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19801454}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19801454}, day = {2}, doi = {10.1152/ajplung.00007.2009}, issn = {1522-1504}, journal = {American journal of physiology. Lung cellular and molecular physiology}, keywords = {emt, hif, mt, ros}, month = {October}, posted-at = {2009-10-29 06:08:16}, priority = {2}, title = {HYPOXIA-INDUCED ALVEOLAR EPITHELIAL-MESENCHYMAL TRANSITION REQUIRES MITOCHONDRIAL ROS AND HYPOXIA-INDUCIBLE FACTOR 1.}, url = {http://dx.doi.org/10.1152/ajplung.00007.2009}, year = {2009} }

TY - JOUR ID - citeulike:6031333 L3 - citeulike-article-id:6031333 N2 - Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies suggest that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of alpha smooth muscle actin (alpha-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat and mouse AEC,suggesting that hypoxia induces EMT in AEC. Both severe and moderate hypoxia induce EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced EMT. Moreover, hypoxia-induced expression of alpha-SMA and vimentin was prevented in mitochondria-deficient rho(0) cells, which are incapable of ROS production during hypoxia. CoCl2 and DMOG, two compounds that stabilize HIF-alpha under normoxia, failed to induce alpha-SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1alpha did not induce alpha-SMA. However, loss of HIF-1alpha or HIF-2alpha abolished induction of alpha-SMA mRNA during hypoxia. Hypoxia increased the levels of transforming growth factor-beta1 (TGF-beta1) and pre-incubation of AEC with SB431542, an inhibitor of the TGF-beta1 type I receptor kinase, prevented the hypoxia-induced EMT, suggesting that the process was TGF-beta1 dependent. Furthermore, both ROS and HIF-alpha were necessary for hypoxia-induced TGF-beta1 upregulation. Accordingly, we provide evidence that hypoxia induces EMT of AEC through mitochondrial ROS, HIF and endogenous TGF-beta1 signaling. Key words: alveolar epithelial cells, pulmonary fibrosis, transforming growth factor beta 1. JF - American journal of physiology. Lung cellular and molecular physiology SN - 1522-1504 TI - HYPOXIA-INDUCED ALVEOLAR EPITHELIAL-MESENCHYMAL TRANSITION REQUIRES MITOCHONDRIAL ROS AND HYPOXIA-INDUCIBLE FACTOR 1. KW - emt KW - hif KW - mt KW - ros AU - Zhou, Guofei AU - Dada, Laura AU - Wu, Minghua AU - Kelly, Aileen AU - Trejo, Humberto AU - Zhou, Qiyuan AU - Varga, John AU - Sznajder, Jacob Iasha PY - 2009/10/02/ UR - http://dx.doi.org/10.1152/ajplung.00007.2009 ER -