title: Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1.
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.
authors.affiliation: Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ha
authors.affiliation: Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Sung Ji
authors.initials: SJ
authors.lastname: Yun
authors.affiliation: Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Jin
authors.affiliation: Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Sang Heon
authors.initials: SH
authors.lastname: Song
authors.affiliation: Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea. Electronic address: sunsik@pusan.ac.kr.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C572458:Rptor protein, rat; C550254:rictor protein, rat; D000804:Angiotensin II; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: PDGF; Phenotype; Rapamycin; VSMC; mTOR