Short communication ICAM-1 and p38 MAPK mediate fibrinogen-induced migration of human vascular smooth muscle cells Bernhard H. Rauch a,1 , Birgit Müschenborn a,1 , Marina Braun a , Artur-Aron Weber b , Karsten Schrör a, ⁎ a Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum, Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany b Institut für Pharmakologie, Universität Duisburg-Essen, Universitätsklinikum Essen, Germany Received 10 May 2007; received in revised form 15 August 2007; accepted 28 August 2007 Available online 11 September 2007 Abstract Fibrinogen deposition in the vessel wall represents an independent atherogenic risk factor. In Boyden-chamber assays, fibrinogen concentration-dependently (1–100 μM) induced migration of human vascular smooth muscle cells (SMC). This was inhibited by antibodies to intercellular adhesion molecule-1 (ICAM-1, 10 μg/ml), and by inhibitors of PI3-kinase (LY294002, 10 μM) and MAPK (mitogen-activated protein kinase) p38 (SB203580, 10 μM). The MEK (MAP kinase kinase) inhibitor PD98059 (10 μM) and the GPIIb/IIIa antagonist abciximab (10 μg/ml) had no effect. ICAM-1 antibodies inhibited fibrinogen-induced Akt and p38 phosphorylation. Thus fibrinogen stimulates human SMC migration through binding to ICAM-1 and activation of Akt and p38. © 2007 Elsevier B.V. All rights reserved. Keywords: Fibrinogen; Migration; Human smooth muscle cell; ICAM-1; p38 MAPK 1. Introduction Fibrinogen is a large molecule of 340 kDa size, and consists of two sets of the polypeptide chains α, β and γ. Polymerization of fibrinogen monomers into fibrin occurs upon cleavage of fibrinopeptides A and B by thrombin (Standeven et al., 2005). Besides its role in blood clotting, fibrinogen exerts important functions in cellular interactions, inflammatory responses, wound healing, and neoplasia (Standeven et al., 2005). Fibrinogen is deposited at sites of atherosclerotic lesions in the vessel wall and hyperfibrinogenemia is considered as an independent atherogenic risk factor (Koenig, 2003). In endothelial cells, interaction of fibrinogen with the intercellular adhesion molecule-1 (ICAM-1) mediates leuko- cyte adhesion and trans-endothelial invasion (Duperray et al., 1997). In smooth muscle cells (SMC), fibrinogen promotes migration (Naito et al., 1989) while its degradation products induce SMC proliferation (Naito et al., 2000). SMC also express ICAM-1 in response to inflammatory stimuli such as TNFα (Braun et al., 1995) and in pathological conditions such as atherosclerosis, restenosis and transplant vasculopathy (Braun et al., 1999). Fibrinogen-ICAM-1 interactions may therefore contribute to SMC proliferation and migration to promote vascular lesion formation. Important intracellular pathways involved in cell proliferation and migration are the PI3-kinase (PI3K)/protein kinase B (Akt) and the stress-activated mitogen- activated protein kinase (MAPK) p38 pathway, which are activated simultaneously by multiple signals and are considered key players in vascular disease (Blanc et al., 2003). In the present study, we demonstrate for the first time that the interaction of fibrinogen with ICAM-1 induces chemotaxis in human vascular SMC through activation of Akt and p38 signaling. 2. Materials and methods 2.1. Materials Purified human fibrinogen type-I was obtained from Sigma- Aldrich (München, Germany). Antibodies against phosphorylated extracellular-regulated kinase (ERK), Akt and p38 were from Cell Available online at www.sciencedirect.com European Journal of Pharmacology 577 (2007) 54 – 57 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Tel.: +49 211 81 12500; fax: +49 211 81 14781. E-mail address: kschroer@uni-duesseldorf.de (K. Schrör). 1 Both authors contributed equally. 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.08.041