PMID- 33412209
OWN - NLM
STAT- MEDLINE
DCOM- 20210302
LR  - 20231213
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 267
DP  - 2021 Feb 15
TI  - Regulation of autophagy by controlling Erk1/2 and mTOR for platelet-derived 
      growth factor-BB-mediated vascular smooth muscle cell phenotype shift.
PG  - 118978
LID - S0024-3205(20)31738-0 [pii]
LID - 10.1016/j.lfs.2020.118978 [doi]
AB  - AIMS: Vascular smooth muscle cell (VSMC) phenotype shift is involved in the 
      pathophysiology of vascular injury or platelet-derived growth factor 
      (PDGF)-induced abnormal proliferation and migration of VSMCs. We aimed to 
      investigate the underlying mechanism involved in PDGF-mediated signaling pathways 
      and autophagy regulation followed by VSMC phenotype shift. MAIN METHODS: The 
      proliferation, migration and apoptosis of cultured rat aortic VSMCs were 
      measured, and cells undergoing phenotype shift and autophagy were examined. 
      Specific inhibitors for target proteins in signaling pathways were applied to 
      clarify their roles in regulating cell functions. KEY FINDINGS: PDGF-BB 
      stimulation initiated autophagy activation and synthetic phenotype transition by 
      decreasing alpha-smooth muscle-actin (SMA), calponin and myosin heavy chain (MHC) and 
      increasing osteopontin (OPN) expression. However, U0126, a potent extracellular 
      signal-regulated kinase 1/2 (Erk1/2) inhibitor, decreased PDGF-BB-induced LC3 
      expression, while rapamycin, an inhibitor of the mammalian target of rapamycin 
      (mTOR), increased it. Furthermore, U0126 decreased the expresseion of 
      autophagy-related genes (Atgs) such as beclin-1, Atg7, Atg5, and Atg12-Atg5 
      complex, indicating that Erk1/2 is a regulator of PDGF-BB-induced VSMC autophagy. 
      Regardless of autophagy inhibition by U0126 or activation by rapamycin, the 
      PDGF-BB-induced decrease in SMA, calponin and MHC and increase in OPN expression 
      were inhibited. Furthermore, PDGF-BB-stimulated VSMC proliferation, migration and 
      proliferating cell nuclear antigen (PCNA) expression were inhibited by U0126 and 
      rapamycin. SIGNIFICANCE: These findings suggest that PDGF-BB-induced autophagy is 
      strongly regulated by Erk1/2, an mTOR-independent pathway, and any approach for 
      targeting autophagy modulation is a potential therapeutic strategy for addressing 
      abnormal VSMC proliferation and migration.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Han, Joo-Hui
AU  - Han JH
AD  - Department of Pharmacology, Chungnam National University College of Pharmacy, 
      Daejeon 34134, Republic of Korea; Institute of Drug Research & Development, 
      Chungnam National University, Daejeon 34134, Republic of Korea.
FAU - Park, Hyun-Soo
AU  - Park HS
AD  - Department of Pharmacology, Chungnam National University College of Pharmacy, 
      Daejeon 34134, Republic of Korea.
FAU - Lee, Do-Hyung
AU  - Lee DH
AD  - Department of Pharmacology, Chungnam National University College of Pharmacy, 
      Daejeon 34134, Republic of Korea.
FAU - Jo, Jun-Hwan
AU  - Jo JH
AD  - Department of Pharmacology, Chungnam National University College of Pharmacy, 
      Daejeon 34134, Republic of Korea.
FAU - Heo, Kyung-Sun
AU  - Heo KS
AD  - Department of Pharmacology, Chungnam National University College of Pharmacy, 
      Daejeon 34134, Republic of Korea.
FAU - Myung, Chang-Seon
AU  - Myung CS
AD  - Department of Pharmacology, Chungnam National University College of Pharmacy, 
      Daejeon 34134, Republic of Korea; Institute of Drug Research & Development, 
      Chungnam National University, Daejeon 34134, Republic of Korea. Electronic 
      address: cm8r@cnu.ac.kr.
LA  - eng
PT  - Journal Article
DEP - 20210105
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (Proliferating Cell Nuclear Antigen)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 1B56C968OA (Becaplermin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 3.6.4.1 (Myosins)
SB  - IM
MH  - Animals
MH  - Autophagy/*physiology
MH  - Becaplermin/genetics/*metabolism/pharmacology
MH  - Calcium-Binding Proteins
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - MAP Kinase Signaling System/physiology
MH  - Microfilament Proteins
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Muscle, Smooth, Vascular/*metabolism
MH  - Myocytes, Smooth Muscle/metabolism
MH  - Myosins
MH  - Phenotype
MH  - Proliferating Cell Nuclear Antigen/metabolism
MH  - Proto-Oncogene Proteins c-sis/metabolism
MH  - Rats
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Calponins
OTO - NOTNLM
OT  - Autophagy
OT  - Erk1/2
OT  - PDGF-BB
OT  - Phenotype shift
OT  - VSMC
OT  - mTOR
EDAT- 2021/01/08 06:00
MHDA- 2021/03/03 06:00
CRDT- 2021/01/07 20:11
PHST- 2020/09/22 00:00 [received]
PHST- 2020/12/16 00:00 [revised]
PHST- 2020/12/22 00:00 [accepted]
PHST- 2021/01/08 06:00 [pubmed]
PHST- 2021/03/03 06:00 [medline]
PHST- 2021/01/07 20:11 [entrez]
AID - S0024-3205(20)31738-0 [pii]
AID - 10.1016/j.lfs.2020.118978 [doi]
PST - ppublish
SO  - Life Sci. 2021 Feb 15;267:118978. doi: 10.1016/j.lfs.2020.118978. Epub 2021 Jan 
      5.