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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

@article{a34d6a0ac4544e3caca1b7da434e59e1,
title = "Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling",
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. ",
keywords = "α2-antiplasmin, airway wall remodelling, annexin A2 hetero-tetramer, asthma, EGF, plasmin",
author = "Stewart, {A G} and Yuxiu Xia and Trudi Harris and S. Royce and Hamilton, {J A} and M. Schuliga",
year = "2013",
month = "12",
doi = "10.1111/bph.12422",
language = "English",
volume = "170",
pages = "1421--1435",
journal = "British Journal of Pharmacology",
issn = "1476-5381",
publisher = "Wiley-Blackwell",
number = "7",

}

Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling. / Stewart, A G; Xia, Yuxiu; Harris, Trudi; Royce, S.; Hamilton, J A; Schuliga, M.

In: British Journal of Pharmacology, Vol. 170, No. 7, 12.2013, p. 1421-1435.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling

AU - Stewart, A G

AU - Xia, Yuxiu

AU - Harris, Trudi

AU - Royce, S.

AU - Hamilton, J A

AU - Schuliga, M.

PY - 2013/12

Y1 - 2013/12

N2 - 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. 

AB - 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. 

KW - α2-antiplasmin

KW - airway wall remodelling

KW - annexin A2 hetero-tetramer

KW - asthma

KW - EGF

KW - plasmin

UR - http://www.scopus.com/inward/record.url?scp=84887653837&partnerID=8YFLogxK

U2 - 10.1111/bph.12422

DO - 10.1111/bph.12422

M3 - Article

VL - 170

SP - 1421

EP - 1435

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 7

ER -