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1 May 2006 MATRIX METALLOPROTEINASE-7 AND EPIDERMAL GROWTH FACTOR RECEPTOR MEDIATE HYPOXIA-INDUCED EXTRACELLULAR SIGNAL-REGULATED KINASE 1/2 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION AND SUBSEQUENT PROLIFERATION IN BLADDER SMOOTH MUSCLE CELLS
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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.
NESRIN SABHA, KAREN AITKEN, ARMANDO J. LORENZO, MARTA SZYBOWSKA, ASHISH JAIRATH and DARIUS J. BÄGLI "MATRIX METALLOPROTEINASE-7 AND EPIDERMAL GROWTH FACTOR RECEPTOR MEDIATE HYPOXIA-INDUCED EXTRACELLULAR SIGNAL-REGULATED KINASE 1/2 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION AND SUBSEQUENT PROLIFERATION IN BLADDER SMOOTH MUSCLE CELLS," In Vitro Cellular & Developmental Biology - Animal 42(5), (1 May 2006). https://doi.org/10.1290/0510070.1
Received: 13 October 2005; Accepted: 22 February 2006; Published: 1 May 2006
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