Genistein inhibits PDGF-stimulated proteoglycan synthesis in vascular smooth muscle without blocking PDGFβ receptor phosphorylation

Suramin inhibits PDGF-stimulated receptor phosphorylation, proteoglycan synthesis and glycosaminoglycan hyperelongation in human vascular smooth muscle cells

“…In earlier work we found that genistein could block PDGF receptor kinase activity in direct kinase assays in vitro but it did not block PDGFβ receptor phosphorylation in VSMCs . Consequently genistein did not block the downstream events of hyperelongation of GAG chains on proteoglycans . Therefore, we evaluated the ability of suramin to attenuate PDGF‐stimulated PDGFβ receptor phosphorylation in human VSMCs.…”

“…We assessed the effects of suramin compared with other known inhibitors of the actions of PDGF, namely, genistein and AG1478. Of note, genistein inhibits some PDGF responses but it does not inhibit PDGF‐stimulated GAG elongation . Cells were treated and labelled as above with xyloside (0.5 m m ) added to the indicated wells.…”

“…PDGF‐stimulated proteoglycan synthesis has been an area of controversy for some time because the GAG elongation effect of PDGF was not blocked by the prototypical antagonist genistein leading to suggestions that the response was not dependent on PDGFβ receptor kinase activity . We recently partially resolved this anomaly by reporting that genistein does not block PDGFβ receptor autophosphorylation in VSMCs . We also demonstrated that imatinib and Ki11502, two well‐characterised PDGF inhibitors, blocked PDGFβ receptor phosphorylation at both the autophosphorylation site and two other docking and signalling sites in the cytoplasmic domain .…”

“…Although our data strongly indicate that suramin inhibits the PDGF–PDGFβ receptor interaction and subsequent receptor activation and downstream signalling, it does not reveal which of the three possible mechanisms contribute to the outcome. These three possible mechanisms are: (1) the antibody‐like action of an interaction with the receptor, thus preventing the ligand‐to‐receptor interaction; (2) an alternative mechanism targeted at binding and inactivating the ligand (PDGF) itself and now we can include (3) direct inhibition of PDGFβ receptor kinase activity …”

(S)-[6]-Gingerol inhibits TGF-β-stimulated biglycan synthesis but not glycosaminoglycan hyperelongation in human vascular smooth muscle cells

“…This raises an interesting question of pharmacology and cell biology as to the mechanism of the inhibitory action of ( S )‐[6]‐gingerol. At this time we can only speculate on the mechanism of inhibition, based by analogy on the effect of genistein on PDGF‐stimulated proliferation of VSMCs and the inhibition of proteoglycan synthesis . In this latter example, PDGF stimulation of VSMCs leads to PDGF receptor phosphorylation and, downstream, a fall in the levels of p27 kip1 as an obligatory step in cell cycle progression .…”