title: Gangliosides GM1, GM2 and GM3 inhibit the platelet-derived growth factor-induced signalling transduction pathway in vascular smooth muscle cells by different mechanisms.
abstract: Gangliosides appear to regulate proliferation of different cell types. In the present study, we investigated the effects of gangliosides GM1, GM2 and GM3 on platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell (VSMC) growth. In addition, we examined the effects of gangliosides on the PDGF-BB-dependent signalling transduction pathway in rat aortic VSMC. GM2 and GM1 inhibit the PDGF-BB-dependent receptor tyrosine autophosphorylation, stimulation of the PLC-gamma 1, increase of inositol-1,4,5-trisphosphate (InsP3), elevation in cytosolic free Ca2+ ([Ca2+]i), expression of the immediate early growth response gene c-fos and cell proliferation with the following rank order of potency GM2 > GM1. Although GM3 did not influence the PDGF-BB-dependent receptor autophosphorylation and PLC-gamma 1 activation, it effectively inhibited the PDGF-BB-dependent InsP3 formation, [Ca2+]i and cell growth. Binding studies with 125I-PDGF-BB on VSMC in the presence and absence of 10 to 50 microM of each ganglioside revealed that GM1 and GM2 effectively inhibited the specific binding of PDGF-BB with an IC50 value of 20 microM for GM2 and 30 microM for GM1. GM3 had no significant effect on the specific 125I-PDGF-BB binding. These observations suggest that GM1 and GM2 may interact with PDGF-BB or its receptor resulting in a prevention of its binding. GM3 was able to suppress the PDGF-BB-dependent increase of InsP3 and [Ca2+]i downstream of the PDGF-BB-dependent receptor autophosphorylation and PLC-gamma 1 activity.
authors.affiliation: Medizinische Universitäts-Poliklinik, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sachinidis
authors.forename: R
authors.initials: R
authors.lastname: Kraus
authors.forename: C
authors.initials: C
authors.lastname: Seul
authors.forename: M K
authors.initials: MK
authors.lastname: Meyer zu Brickwedde
authors.forename: K
authors.initials: K
authors.lastname: Schulte
authors.forename: Y
authors.initials: Y
authors.lastname: Ko
authors.forename: J
authors.initials: J
authors.lastname: Hoppe
authors.forename: H
authors.initials: H
authors.lastname: Vetter
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D005678:G(M2) Ganglioside / Q000494:pharmacology*; D005679:G(M3) Ganglioside / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000032:analysis; D007527:Isoenzymes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011921:Rats, Inbred WKY; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D005679:G(M3) Ganglioside; D007295:Inositol Phosphates; D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D016760:Proto-Oncogene Proteins c-fos; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D005678:G(M2) Ganglioside; D000077214:Becaplermin; D005677:G(M1) Ganglioside; D020794:Receptor Protein-Tyrosine Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium