title: 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.
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.
authors.affiliation: Division of Infection, Immunity, Injury, & Repair, The Research Institute, The Hospital for Sick Children and Institute for Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.forename: Karen
authors.initials: K
authors.lastname: Aitken
authors.forename: Armando J
authors.initials: AJ
authors.lastname: Lorenzo
authors.forename: Marta
authors.initials: M
authors.lastname: Szybowska
authors.forename: Ashish
authors.initials: A
authors.lastname: Jairath
authors.forename: Darius J
authors.initials: DJ
authors.lastname: Bägli
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism* / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000502:physiology; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000166:cytology*
chemical_list: D005419:Flavonoids; D012333:RNA, Messenger; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D020783:Matrix Metalloproteinase 7; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one