Platelet-derived growth factor-stimulated versican synthesis but not glycosaminoglycan elongation in vascular smooth muscle is mediated via Akt phosphorylation.
Proteoglycans are associated with the initiation of atherosclerosis due to their binding of apolipoproteins on lipid particles leading to retention in the vessel wall. The signaling pathways through which growth factors regulate the synthesis and structure of proteoglycans are potential therapeutic targets. Platelet-derived growth factor (PDGF) is present in atherosclerotic plaques and activates phosphorylation of the serine/threonine kinase Akt. We have investigated the role of Akt in the signaling pathways for proteoglycan core protein expression and elongation of glycosaminoglycan chains on proteoglycans secreted by human vascular smooth muscle cells. The pharmacological inhibitor of Akt phosphorylation, SN30978, blocked PDGF stimulated phosphorylation of Akt. SN30978 caused concentration dependent inhibition of PDGF stimulated radiosulfate incorporation into secreted proteoglycans and the response was blocked by the PDGF receptor antagonists Ki11502 and imatinib. Analysis of the size of the biglycan molecules by SDS-PAGE showed that PDGF increased the apparent size of biglycan but this effect on glycosaminoglycan chain elongation was blocked by Ki11502 but not by SN30978. PDGF also stimulated total protein core protein synthesis assessed as (35)S-methionine/cysteine incorporation and specifically the expression of versican mRNA. Both of these responses were blocked by SN30978. This data shows that PDGF-stimulated proteoglycan core protein synthesis but not glycosaminoglycan chain elongation is mediated via Akt phosphorylation. These data identify potential pathways for the development of agents which can pharmacologically regulate individual components of the synthesis of proteoglycans.
Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia; Monash University, Departments of Medicine and Immunology, Central and Eastern Clinical School, Alfred Health, Melbourne, VIC, Australia. Electronic address: narin.osman@rmit.edu.au.
Narin
N
Osman
Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia.
Robel
R
Getachew
Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia.
Lyna
L
Thach
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Haitao
H
Wang
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Xiaoying
X
Su
Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Wenhua
W
Zheng
Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083, Australia; Monash University, Departments of Medicine and Immunology, Central and Eastern Clinical School, Alfred Health, Melbourne, VIC, Australia.
Peter J
PJ
Little
D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D053675:Versicans / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D006025:Glycosaminoglycans; C529896:Ki11502; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D011804:Quinolines; D012333:RNA, Messenger; D053675:Versicans; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt
Akt; Atherosclerosis; GAG hyperelongation; Platelet-derived growth factor; Proteoglycans