PMID- 36108736
OWN - NLM
STAT- MEDLINE
DCOM- 20221006
LR  - 20221006
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 933
DP  - 2022 Oct 15
TI  - Transcription factor EB protects against endoplasmic reticulum stress in human 
      coronary artery endothelial cells.
PG  - 175274
LID - S0014-2999(22)00535-0 [pii]
LID - 10.1016/j.ejphar.2022.175274 [doi]
AB  - Oxidative stress and endoplasmic reticulum (ER) stress promote atherogenesis 
      while transcription factor EB (TFEB) inhibits atherosclerosis. Since reducing 
      oxidative stress with antioxidants have failed to reduce atherosclerosis possibly 
      because of aggravation of ER stress, we studied the effect of TFEB on ER stress 
      in human coronary artery endothelial cells. ER stress was measured using the 
      secreted alkaline phosphatase assay. Expression and phosphorylation of key 
      mediators of unfolded protein response (UPR). TFEB, inositol-requiring enzyme 1alpha 
      (IRE1alpha), phospho-IRE1alpha, protein kinase R (PKR)-like endoplasmic reticulum kinase 
      (PERK), phospho-PERK, and activating transcription factor 6 (ATF6) expression 
      were measured by Western blot. The effect of TFEB gain- and loss-of-function on 
      ER stress were assessed with a plasmid expressing a constitutively active form of 
      TFEB and via siRNA-mediated silencing, respectively. Treatment with tunicamycin 
      (TM) and thapsigargin (TG) increased TFEB expression by 42.8% and 42.3%, 
      respectively. In HCAEC transfected with the TFEB siRNA, treatment with either TM, 
      TG or high-dextrose increased IRE1alpha and PERK phosphorylation and ATF6 levels 
      significantly more compared to cells transfected with the control siRNA and 
      treated similarly. Furthermore, transient transfection with a plasmid expressing 
      a constitutively active form of TFEB reduced ER stress. Increased expression of 
      TFEB inhibited ER stress in HCAEC treated with pharmacologic (TM and TG) and 
      physiologic (high-dextrose) ER stress inducers, while TFEB knockout aggravated ER 
      stress caused by these ER stress inducers. TFEB-mediated ER stress reduction may 
      contribute to its anti-atherogenic effects in HCAEC and may be a novel target for 
      drug development.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Haas, Michael J
AU  - Haas MJ
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Florida Jacksonville College of Medicine, Jacksonville, FL, 32209, 
      USA. Electronic address: Michael.haas@jax.ufl.edu.
FAU - Feng, Victoria
AU  - Feng V
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Florida Jacksonville College of Medicine, Jacksonville, FL, 32209, 
      USA.
FAU - Gonzales, Krista
AU  - Gonzales K
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Florida Jacksonville College of Medicine, Jacksonville, FL, 32209, 
      USA.
FAU - Bikkina, Priyanka
AU  - Bikkina P
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Florida Jacksonville College of Medicine, Jacksonville, FL, 32209, 
      USA.
FAU - Angelica Landicho, Marie
AU  - Angelica Landicho M
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Florida Jacksonville College of Medicine, Jacksonville, FL, 32209, 
      USA.
FAU - Mooradian, Arshag D
AU  - Mooradian AD
AD  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 
      University of Florida Jacksonville College of Medicine, Jacksonville, FL, 32209, 
      USA.
LA  - eng
PT  - Journal Article
DEP - 20220913
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (RNA, Small Interfering)
RN  - 11089-65-9 (Tunicamycin)
RN  - 4L6452S749 (Inositol)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.1.- (Endoribonucleases)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Activating Transcription Factor 6/genetics/metabolism
MH  - Alkaline Phosphatase/metabolism
MH  - *Atherosclerosis
MH  - Coronary Vessels/metabolism
MH  - *Endoplasmic Reticulum Stress
MH  - Endoribonucleases/genetics/metabolism
MH  - Endothelial Cells/metabolism
MH  - Glucose/pharmacology
MH  - Humans
MH  - Inositol/pharmacology
MH  - Protein Serine-Threonine Kinases/genetics
MH  - RNA, Small Interfering/metabolism
MH  - Thapsigargin/pharmacology
MH  - Tunicamycin/pharmacology
MH  - Unfolded Protein Response
MH  - eIF-2 Kinase/genetics/metabolism
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Cardiovascular disease
OT  - ER Stress
OT  - HCAEC
OT  - Transcription factor EB
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/09/16 06:00
MHDA- 2022/10/07 06:00
CRDT- 2022/09/15 19:23
PHST- 2022/06/15 00:00 [received]
PHST- 2022/08/24 00:00 [revised]
PHST- 2022/09/08 00:00 [accepted]
PHST- 2022/09/16 06:00 [pubmed]
PHST- 2022/10/07 06:00 [medline]
PHST- 2022/09/15 19:23 [entrez]
AID - S0014-2999(22)00535-0 [pii]
AID - 10.1016/j.ejphar.2022.175274 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2022 Oct 15;933:175274. doi: 10.1016/j.ejphar.2022.175274. Epub 
      2022 Sep 13.