Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling

A G Stewart, Yuxiu Xia, Trudi Harris, S. Royce, J A Hamilton, M. Schuliga

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14 Citations (Scopus)

Abstract

Background and Purpose: The conversion of plasminogen into plasmin by interstitial urokinase plasminogen activator (uPA) is potentially important in asthma pathophysiology. In this study, the effect of uPA-mediated plasminogen activation on airway smooth muscle (ASM) cell proliferation was investigated. 

Experimental Approach: Human ASM cells were incubated with plasminogen (0.5-50 μg·mL-1) or plasmin (0.5-50 mU·mL-1) in the presence of pharmacological inhibitors, including UK122, an inhibitor of uPA. Proliferation was assessed by increases in cell number or MTT reduction after 48 h incubation with plasmin(ogen), and by earlier increases in [ 3H]-thymidine incorporation and cyclin D1 expression. 

Key Results: Plasminogen (5 μg·mL-1)-stimulated increases in cell proliferation were attenuated by UK122 (10 μM) or by transfection with uPA gene-specific siRNA. Exogenous plasmin (5 mU·mL-1) also stimulated increases in cell proliferation. Inhibition of plasmin-stimulated ERK1/2 or PI3K/Akt signalling attenuated plasmin-stimulated increases in ASM proliferation. Furthermore, pharmacological inhibition of cell signalling mediated by the EGF receptor, a receptor trans-activated by plasmin, also reduced plasmin(ogen)-stimulated cell proliferation. Knock down of annexin A2, which has dual roles in both plasminogen activation and plasmin-signal transduction, also attenuated ASM cell proliferation following incubation with either plasminogen or plasmin. 

Conclusions and Implications: Plasminogen stimulates ASM cell proliferation in a manner mediated by uPA and involving multiple signalling pathways downstream of plasmin. Targeting mediators of plasminogen-evoked ASM responses, such as uPA or annexin A2, may be useful in the treatment of asthma. 

Original languageEnglish
Pages (from-to)1421-1435
Number of pages15
JournalBritish Journal of Pharmacology
Volume170
Issue number7
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

Keywords

  • α2-antiplasmin
  • airway wall remodelling
  • annexin A2 hetero-tetramer
  • asthma
  • EGF
  • plasmin

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