Abstract
Urotensin II (U-II) is implicated in vascular smooth muscle cell proliferation, which results in vascular remodeling. We recently demonstrated that both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in U-II signal transduction. However, the detailed intracellular mechanism of U-II in vascular smooth muscle cells remains unclear. In this study, we used rat aortic smooth muscle cells treated with U-II to investigate the connection between ROS generation and EGFR transactivation. U-II treatment was found to stimulate endothelin-1 (ET-1) expression and cell proliferation through the phosphorylation of EGFR and ROS generation. NAD(P)H oxidase inhibitor apocynin and ROS scavenger N-acetylcysteine (NAC) inhibited the EGFR transactivation induced by U-II. In contrast, AG-1478 (an EGFR inhibitor) failed to inhibit intracellular ROS generation induced by U-II. Src homology 2-containing tyrosine phosphatase (SHP-2) was shown to be associated with EGFR during U-II treatment by EGFR coimmunoprecipitation. ROS have been reported to oxidize the catalytic cysteine of SHP-2 and inhibit its activity. We examined the effect of U-II on SHP-2 in smooth muscle cells using a modified malachite green phosphatase assay. SHP-2 was oxidized during U-II treatment; and this oxidization could be repressed by NAC treatment. In SHP-2 knockdown cells, U-II-induced EGFR phosphorylation, ET-1 secretion, and cell proliferation were enhanced, and were not influenced by NAC. Our data suggest that U-II-mediated ROS generation can inhibit SHP-2 activity to facilitate the EGFR transactivation and mitogenic signal transduction in rat aortic smooth muscle cells.
| Original language | English |
|---|---|
| Pages (from-to) | 86-94 |
| Number of pages | 9 |
| Journal | Atherosclerosis |
| Volume | 206 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Sep 2009 |
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Keywords
- Endothelin-1
- Epidermal growth factor receptor transactivation
- Reactive oxygen species
- Smooth muscle cell proliferation
- Src homology 2-containing phosphotyrosine phosphatase
- Urotensin II
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Cite this
Urotensin II-induced endothelin-1 expression and cell proliferation via epidermal growth factor receptor transactivation in rat aortic smooth muscle cells. / Tsai, Chien Sung; Loh, Shih Hurng; Liu, Ju Chi; Lin, Jia Wei; Chen, Yen Ling; Chen, Cheng Hsien; Cheng, Tzu-Hurng.
In: Atherosclerosis, Vol. 206, No. 1, 09.2009, p. 86-94.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Urotensin II-induced endothelin-1 expression and cell proliferation via epidermal growth factor receptor transactivation in rat aortic smooth muscle cells
AU - Tsai, Chien Sung
AU - Loh, Shih Hurng
AU - Liu, Ju Chi
AU - Lin, Jia Wei
AU - Chen, Yen Ling
AU - Chen, Cheng Hsien
AU - Cheng, Tzu-Hurng
PY - 2009/9
Y1 - 2009/9
N2 - Urotensin II (U-II) is implicated in vascular smooth muscle cell proliferation, which results in vascular remodeling. We recently demonstrated that both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in U-II signal transduction. However, the detailed intracellular mechanism of U-II in vascular smooth muscle cells remains unclear. In this study, we used rat aortic smooth muscle cells treated with U-II to investigate the connection between ROS generation and EGFR transactivation. U-II treatment was found to stimulate endothelin-1 (ET-1) expression and cell proliferation through the phosphorylation of EGFR and ROS generation. NAD(P)H oxidase inhibitor apocynin and ROS scavenger N-acetylcysteine (NAC) inhibited the EGFR transactivation induced by U-II. In contrast, AG-1478 (an EGFR inhibitor) failed to inhibit intracellular ROS generation induced by U-II. Src homology 2-containing tyrosine phosphatase (SHP-2) was shown to be associated with EGFR during U-II treatment by EGFR coimmunoprecipitation. ROS have been reported to oxidize the catalytic cysteine of SHP-2 and inhibit its activity. We examined the effect of U-II on SHP-2 in smooth muscle cells using a modified malachite green phosphatase assay. SHP-2 was oxidized during U-II treatment; and this oxidization could be repressed by NAC treatment. In SHP-2 knockdown cells, U-II-induced EGFR phosphorylation, ET-1 secretion, and cell proliferation were enhanced, and were not influenced by NAC. Our data suggest that U-II-mediated ROS generation can inhibit SHP-2 activity to facilitate the EGFR transactivation and mitogenic signal transduction in rat aortic smooth muscle cells.
AB - Urotensin II (U-II) is implicated in vascular smooth muscle cell proliferation, which results in vascular remodeling. We recently demonstrated that both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in U-II signal transduction. However, the detailed intracellular mechanism of U-II in vascular smooth muscle cells remains unclear. In this study, we used rat aortic smooth muscle cells treated with U-II to investigate the connection between ROS generation and EGFR transactivation. U-II treatment was found to stimulate endothelin-1 (ET-1) expression and cell proliferation through the phosphorylation of EGFR and ROS generation. NAD(P)H oxidase inhibitor apocynin and ROS scavenger N-acetylcysteine (NAC) inhibited the EGFR transactivation induced by U-II. In contrast, AG-1478 (an EGFR inhibitor) failed to inhibit intracellular ROS generation induced by U-II. Src homology 2-containing tyrosine phosphatase (SHP-2) was shown to be associated with EGFR during U-II treatment by EGFR coimmunoprecipitation. ROS have been reported to oxidize the catalytic cysteine of SHP-2 and inhibit its activity. We examined the effect of U-II on SHP-2 in smooth muscle cells using a modified malachite green phosphatase assay. SHP-2 was oxidized during U-II treatment; and this oxidization could be repressed by NAC treatment. In SHP-2 knockdown cells, U-II-induced EGFR phosphorylation, ET-1 secretion, and cell proliferation were enhanced, and were not influenced by NAC. Our data suggest that U-II-mediated ROS generation can inhibit SHP-2 activity to facilitate the EGFR transactivation and mitogenic signal transduction in rat aortic smooth muscle cells.
KW - Endothelin-1
KW - Epidermal growth factor receptor transactivation
KW - Reactive oxygen species
KW - Smooth muscle cell proliferation
KW - Src homology 2-containing phosphotyrosine phosphatase
KW - Urotensin II
UR - http://www.scopus.com/inward/record.url?scp=68949206488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68949206488&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2009.02.013
DO - 10.1016/j.atherosclerosis.2009.02.013
M3 - Article
VL - 206
SP - 86
EP - 94
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
IS - 1
ER -