Abstract
Modulation of the vascular smooth-muscle-cell (vSMC) phenotype from a quiescent 'contractile' phenotype to a proliferative 'synthetic' phenotype has been implicated in vascular injury repair, as well as pathogenesis of vascular proliferative diseases. Both bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta)-signalling pathways promote a contractile phenotype, while the platelet-derived growth factor-BB (PDGF-BB)-signalling pathway promotes a switch to the synthetic phenotype. Here we show that PDGF-BB induces microRNA-24 (miR-24), which in turn leads to downregulation of Tribbles-like protein-3 (Trb3). Repression of Trb3 coincides with reduced expression of Smad proteins and decrease in BMP and TGFbeta signalling, promoting a synthetic phenotype in vSMCs. Inhibition of miR-24 by antisense oligonuclotides abrogates the downregulation of Trb3 as well as pro-synthetic activity of the PDGF-signalling pathway. Thus, this study provides a molecular basis for the antagonism between the PDGF and TGFbeta pathways, and its effect on the control of the vSMC phenotype.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Becaplermin
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COS Cells
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Cells, Cultured
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Chlorocebus aethiops
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Drug Antagonism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Humans
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Male
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Mice
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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MicroRNAs / physiology
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Mink
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Models, Biological
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Muscle Contraction / drug effects
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Muscle Contraction / genetics
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism
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Myocytes, Smooth Muscle / physiology
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Platelet-Derived Growth Factor / antagonists & inhibitors*
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Platelet-Derived Growth Factor / pharmacology
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Platelet-Derived Growth Factor / physiology
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-sis
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta / physiology
Substances
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MIRN24 microRNA, human
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MIRN24 microRNA, rat
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MicroRNAs
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Transforming Growth Factor beta
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Trib3 protein, rat
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Becaplermin
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Protein Kinases
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Protein Serine-Threonine Kinases