Abstract
Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs.
Keywords:
PDGF; Phenotype; Rapamycin; VSMC; mTOR.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / pharmacology
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Animals
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Aorta / cytology
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Aorta / drug effects
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Aorta / metabolism
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / genetics*
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Multiprotein Complexes / metabolism
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / metabolism
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / metabolism
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Phenotype
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism
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Platelet-Derived Growth Factor / pharmacology*
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Primary Cell Culture
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rapamycin-Insensitive Companion of mTOR Protein
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Rats
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Rats, Sprague-Dawley
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Regulatory-Associated Protein of mTOR
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Phosphoproteins
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Platelet-Derived Growth Factor
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RNA, Small Interfering
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Rapamycin-Insensitive Companion of mTOR Protein
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Regulatory-Associated Protein of mTOR
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Rptor protein, rat
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rictor protein, rat
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Angiotensin II
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mTOR protein, rat
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Sirolimus