Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions
Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a pote...
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PeerJ Inc.
2013-11-01
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| author | Kengo Suzuki Kenichiro Nishi Satoshi Takabuchi Shinichi Kai Tomonori Matsuyama Shin Kurosawa Takehiko Adachi Takayuki Maruyama Kazuhiko Fukuda Kiichi Hirota |
| author_facet | Kengo Suzuki Kenichiro Nishi Satoshi Takabuchi Shinichi Kai Tomonori Matsuyama Shin Kurosawa Takehiko Adachi Takayuki Maruyama Kazuhiko Fukuda Kiichi Hirota |
| author_sort | Kengo Suzuki |
| collection | DOAJ |
| description | Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation. |
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| language | English |
| last_indexed | 2024-03-09T06:39:41Z |
| publishDate | 2013-11-01 |
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| spelling | doaj.art-e209dd91e89e40b68f61251ad141abc22023-12-03T10:53:34ZengPeerJ Inc.PeerJ2167-83592013-11-011e22010.7717/peerj.220220Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditionsKengo Suzuki0Kenichiro Nishi1Satoshi Takabuchi2Shinichi Kai3Tomonori Matsuyama4Shin Kurosawa5Takehiko Adachi6Takayuki Maruyama7Kazuhiko Fukuda8Kiichi Hirota9Department of Anesthesia, Kyoto University Hospital, Kyoto, JapanDepartment of Anesthesiology, Kansai Medical University, Hirakata, Osaka, JapanDepartment of Anesthesiology, Kansai Medical University, Hirakata, Osaka, JapanDepartment of Anesthesia, Kyoto University Hospital, Kyoto, JapanDepartment of Anesthesia, Kyoto University Hospital, Kyoto, JapanDepartment of Anesthesiology, Tohoku University Hospital, Sendai, JapanDepartment of Anesthesia, Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, JapanMinase Research Institutes, Research Headquarters, Ono Pharmaceutical, Osaka, JapanDepartment of Anesthesia, Kyoto University Hospital, Kyoto, JapanDepartment of Anesthesiology, Kansai Medical University, Hirakata, Osaka, JapanProstaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation.https://peerj.com/articles/220.pdfProstaglandin E1AngiogenesisVEGFHypoxia-inducible factorEP receptorHuman endothelial cells |
| spellingShingle | Kengo Suzuki Kenichiro Nishi Satoshi Takabuchi Shinichi Kai Tomonori Matsuyama Shin Kurosawa Takehiko Adachi Takayuki Maruyama Kazuhiko Fukuda Kiichi Hirota Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions PeerJ Prostaglandin E1 Angiogenesis VEGF Hypoxia-inducible factor EP receptor Human endothelial cells |
| title | Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions |
| title_full | Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions |
| title_fullStr | Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions |
| title_full_unstemmed | Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions |
| title_short | Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions |
| title_sort | differential roles of prostaglandin e type receptors in activation of hypoxia inducible factor 1 by prostaglandin e1 in vascular derived cells under non hypoxic conditions |
| topic | Prostaglandin E1 Angiogenesis VEGF Hypoxia-inducible factor EP receptor Human endothelial cells |
| url | https://peerj.com/articles/220.pdf |
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