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 [(3) H]-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.

• Authors: A G Stewart, Y C Xia, T Harris, S Royce, J A Hamilton, M Schuliga
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 7 Pg. 1421-35 (Dec 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 24111848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• ANXA2 protein, human
• Annexin A2
• CCND1 protein, human
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Serine Proteinase Inhibitors
• Cyclin D1
• Plasminogen
• Phosphatidylinositol 3-Kinase
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Fibrinolysin
• Urokinase-Type Plasminogen Activator

Topics

• Annexin A2 (genetics, metabolism)
• Bronchi (drug effects, enzymology, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclin D1 (metabolism)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Fibrinolysin (metabolism)
• Humans
• Hyperplasia
• Muscle, Smooth (drug effects, enzymology, pathology)
• Myocytes, Smooth Muscle (drug effects, enzymology, pathology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Plasminogen (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• RNA Interference
• Serine Proteinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Time Factors
• Transfection
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors, genetics, metabolism)