Abstract |
Low oxygen tension ( hypoxia) has been implicated in proliferation of vascular smooth muscle cells (SMCs) of the lung. Tissue hypoxia also occurs in the obstructed bladder. The extracellular-regulated kinase mitogen-activated protein kinase 1/2 (Erk1/2) pathway is induced in many cell types during hypoxia. We examined whether hypoxia (3% O2), compared with normoxia (21% O2), induces proliferation responses and activation of the Erk1/2 pathways in primary rat bladder smooth muscle cells (BSMCs). We show that hypoxia induces proliferation of BSMCs at 18 h and, although reduced at 22 h, still remained above normoxic levels. Hypoxia induced a strikingly transient activation of Erk1/2 that lasted only 10-30 min. However, inhibition of the transient Erk1/2 activity with a specific mitogen-activated protein kinase kinase 1 (MEK-1) inhibitor PD 98059 prevented subsequent hypoxia-induced proliferation at 18 h. Interestingly, inhibition of general matrix metalloproteinase ( MMP) activity, using either doxycycline or GM 6001, prevented both transient Erk1/2 activity and subsequent proliferation in response to hypoxia. Furthermore, MMP-7 ( matrilysin) is activated in the conditioned medium (CM) of BSMCs at 10-20 min of hypoxia. In addition, MMP-7 was also transcriptionally induced at 6 h of hypoxia in an Erk1/2-dependent manner. Moreover, transient Erk1/2 activation and BSMC proliferation were both dependent on epidermal growth factor receptor (EGFR/HER1) but not neu receptor (HER2/ERB2) autophosphorylation. We conclude that hypoxia leads to Erk1/2 activation, which appears to modulate BSMC proliferation through MMP-7-and EGFR-mediated mechanisms.
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Authors | Nesrin Sabha, Karen Aitken, Armando J Lorenzo, Marta Szybowska, Ashish Jairath, Darius J Bägli |
Journal | In vitro cellular & developmental biology. Animal
(In Vitro Cell Dev Biol Anim)
2006 May-Jun
Vol. 42
Issue 5-6
Pg. 124-33
ISSN: 1071-2690 [Print] Germany |
PMID | 16848631
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Flavonoids
- RNA, Messenger
- ErbB Receptors
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- MAP Kinase Kinase 1
- Matrix Metalloproteinase 7
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Animals
- Cell Hypoxia
- Cell Proliferation
(drug effects)
- Enzyme Activation
- ErbB Receptors
(metabolism, physiology)
- Flavonoids
(pharmacology)
- Gene Expression Regulation
- MAP Kinase Kinase 1
(antagonists & inhibitors)
- MAP Kinase Signaling System
(physiology)
- Matrix Metalloproteinase 7
(genetics, metabolism, physiology)
- Mitogen-Activated Protein Kinase 1
(metabolism)
- Mitogen-Activated Protein Kinase 3
(metabolism)
- Muscle, Smooth
(cytology, drug effects, enzymology)
- Phosphorylation
- RNA, Messenger
(metabolism)
- Rats
- Rats, Sprague-Dawley
- Urinary Bladder
(cytology)
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