Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase.
Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we inves...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4569419?pdf=render |
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| author | Ying-Ju Lai Gwo-Jyh Chang Yung-Hsin Yeh Jong-Hwei S Pang Chung-Chi Huang Wei-Jan Chen |
| author_facet | Ying-Ju Lai Gwo-Jyh Chang Yung-Hsin Yeh Jong-Hwei S Pang Chung-Chi Huang Wei-Jan Chen |
| author_sort | Ying-Ju Lai |
| collection | DOAJ |
| description | Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy. |
| first_indexed | 2024-12-11T19:33:34Z |
| format | Article |
| id | doaj.art-13d9e32a524f4450901727be740c33d4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T19:33:34Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-13d9e32a524f4450901727be740c33d42022-12-22T00:53:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013742610.1371/journal.pone.0137426Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase.Ying-Ju LaiGwo-Jyh ChangYung-Hsin YehJong-Hwei S PangChung-Chi HuangWei-Jan ChenGamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.http://europepmc.org/articles/PMC4569419?pdf=render |
| spellingShingle | Ying-Ju Lai Gwo-Jyh Chang Yung-Hsin Yeh Jong-Hwei S Pang Chung-Chi Huang Wei-Jan Chen Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. PLoS ONE |
| title | Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. |
| title_full | Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. |
| title_fullStr | Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. |
| title_full_unstemmed | Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. |
| title_short | Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. |
| title_sort | propylthiouracil attenuates experimental pulmonary hypertension via suppression of pen 2 a key component of gamma secretase |
| url | http://europepmc.org/articles/PMC4569419?pdf=render |
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