Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation
| Autor: | Gervaise Loirand, Patrice Guérin, Yann Gouëffic, Philippe Patra, Pierre Pacaud, Christophe Guilluy |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Simvastatin
Small interfering RNA RHOA Pyridines Physiology Muscle Smooth Vascular Enterotoxins Phosphatidylinositol 3-Kinases chemistry.chemical_compound Cell Movement LY294002 Hyaluronic Acid RNA Small Interfering Aorta Cells Cultured Cytoskeleton Phosphoinositide-3 Kinase Inhibitors Extracellular Matrix Proteins rho-Associated Kinases Escherichia coli Proteins Intracellular Signaling Peptides and Proteins Antibodies Monoclonal Complement C3 Stimulation Chemical rac GTP-Binding Proteins Cell biology Hyaluronan Receptors Biochemistry RNA Interference Lamellipodium Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction Stress fiber Morpholines Recombinant Fusion Proteins Bacterial Toxins Protein Serine-Threonine Kinases Biology Physiology (medical) Animals Phosphoinositide 3-kinase Dose-Response Relationship Drug Amides Actins Rats chemistry Chromones Genes tat Rho kinase inhibitor biology.protein rhoA GTP-Binding Protein |
| Zdroj: | Cardiovascular Research. 72:339-348 |
| ISSN: | 0008-6363 |
| DOI: | 10.1016/j.cardiores.2006.07.017 |
| Popis: | Objective: Hyaluronan (HA) is an important constituent of the extracellular matrix and is known to regulate cellular events through binding to CD44 and the receptor for HA-mediated motility (RHAMM). Here we investigated the role of these receptors and the signaling pathways involved in HA-mediated effects in arterial smooth muscle cells (ASMC). Methods: Effects of high-molecular weight HA (1 to 5 mg/ml) were analyzed in cultured ASMC from rat aorta. Results: HA promoted actin stress fiber and lamellipodia formation and dose-dependently induced ASMC migration without effect on proliferation. Pull-down assay of Rho protein activity indicated that HA activated RhoA and Rac. HA-induced ASMC migration was not affected by the RhoA inhibitor Tat-C3 (10 μg/ml), the Rho kinase inhibitor Y-27632 (10 μM) and blocking anti-CD44 antibody, but was reduced by the non-selective Rho protein inhibitor simvastatin (10 μM), the Rac inhibitor LT-toxin (1 μg/ml), small interfering RNA (siRNA) targeting Rac and the phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002 (25 μM), which also blocked HA-induced Rac activation. CD44 knockdown by siRNA inhibited HA-mediated RhoA activation without effect on ASMC migration. In contrast, siRNA targeting RHAMM inhibited both HA-induced migration and Rac activation. Conclusions: High-molecular weight HA independently activates RhoA and Rac through CD44 and RHAMM, respectively. HA-induced migration depends exclusively on RHAMM-mediated PI3K-dependent Rac activation. |
| Databáze: | OpenAIRE |
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