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Key role of PI3Kgamma in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration

Fougerat, A. and Smirnova, N. F. and Gayral, S. and Malet, N. and Hirsch, E. and Wymann, M. P. and Perret, B. and Martinez, L. O. and Douillon, M. and Laffargue, M.. (2012) Key role of PI3Kgamma in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration. British journal of pharmacology, Vol. 166, no. 5. pp. 1643-1653.

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Official URL: http://edoc.unibas.ch/dok/A6338014

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Abstract

BACKGROUND AND PURPOSE: Vascular smooth muscle cell (SMC) migration within the arterial wall is a crucial event in atherogenesis and restenosis. Monocyte chemotactic protein-1/CC-chemokine receptor 2 (MCP-1/CCR2) signalling is involved in SMC migration processes but the molecular mechanisms have not been well characterized. We investigated the role of PI3Kgamma in SMC migration induced by MCP-1. EXPERIMENTAL APPROACHES: A pharmacological PI3Kgamma inhibitor, adenovirus encoding inactive forms of PI3Kgamma and genetic deletion of PI3Kgamma were used to investigate PI3Kgamma functions in the MCP-1 and platelet-derived growth factor (PDGF) signalling pathway and migration process in primary aortic SMC. KEY RESULTS: The gamma isoform of PI3K was shown to be the major signalling molecule mediating PKB phosphorylation in MCP-1-stimulated SMC. Using a PI3Kgamma inhibitor and an adenovirus encoding a dominant negative form of PI3Kgamma, we demonstrated that PI3Kgamma is essential for SMC migration triggered by MCP-1. PDGF receptor stimulation induced MCP-1 mRNA and protein accumulation in SMCs. Blockade of the MCP-1/CCR2 pathway or pharmacological inhibition of PI3Kgamma reduced PDGF-stimulated aortic SMC migration by 50%. Thus PDGF promotes an autocrine loop involving MCP-1/CCR2 signalling which is required for PDGF-mediated SMC migration. Furthermore, SMCs isolated from PI3Kgamma-deficient mice (PI3Kgamma(-/-)), or mice expressing an inactive PI3Kgamma (PI3Kgamma(KD/KD)), migrated less than control cells in response to MCP-1 and PDGF. CONCLUSIONS AND IMPLICATIONS: PI3Kgamma is essential for MCP-1-stimulated aortic SMC migration and amplifies cell migration induced by PDGF by an autocrine/paracrine loop involving MCP-1 secretion and CCR2 activation. PI3Kgamma is a promising target for the treatment of aortic fibroproliferative pathologies.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)
UniBasel Contributors:Wymann, Matthias P.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Nature Publishing Group
ISSN:0007-1188
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:13
Deposited On:10 Apr 2015 09:13

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