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

Author:

Little Peter J12,Rostam Muhamad Ashraf1,Piva Terrence J2,Getachew Robel1,Kamato Danielle1,Guidone Daniel1,Ballinger Mandy L3,Zheng Wenhua4,Osman Narin13

Affiliation:

1. Discipline of Pharmacy, School of Medical Sciences, Diabetes Complications Group, Health Innovations Research Institute, Melbourne, VIC, Australia

2. Departments of Medicine and Immunology, Central and Eastern Clinical School, Alfred Health, Monash University, Melbourne, VIC, Australia

3. Discipline of Cell Biology, School of Medical Sciences, RMIT University, Bundoora, Australia

4. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China

Abstract

Abstract Objectives Suramin is a polysulfonated naphthylurea with antiparasitic and potential antineoplastic activity. Suramin's pharmacological actions, which have not yet been fully elucidated, include antagonism of the action of platelet-derived growth factor (PDGF) at its receptor. We investigated the effects of suramin on PDGF-stimulated proteoglycan synthesis. Methods Human vascular smooth muscle cells (VSMCs) were incubated in the presence and absence of PDGF and suramin with [3H]thymidine or 35SO4 as radiolabels. Mitogenic response was determined by [3H]thymidine incorporation. PDGFβ receptor phosphorylation was assessed by western blotting. Proteoglycan size and glycosaminoglycan chain synthesis and size were determined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The Alphascreen phosphotyrosine assay kit was used to investigate PDGFβ receptor tyrosine kinase inhibition by suramin. Key findings Suramin decreased PDGF-stimulated proliferation, proteoglycan synthesis and GAG chain hyperelongation. Suramin also directly inhibited PDGFβ receptor kinase activity as well as PDGFβ receptor phosphorylation in intact VSMCs. Conclusions These data show that inhibition of PDGFβ receptor phosphorylation in intact cells is necessary to define a fully active PDGF antagonist. They also confirm that PDGFβ receptor kinase activity is necessary for PDGF-mediated atherogenic changes in proteoglycan synthesis and support efforts to develop PDGFβ receptor antagonists as potential anti-atherosclerotic agents.

Funder

National Health and Medical Research Council Project Grant

National Heart Foundation of Australia Grant-in-Aid for Research

Diabetes Australia Research Trust

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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