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Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy.

Abstract The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death.
PMID
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Authors

Mayor MeshTerms

Apoptosis

Keywords
Journal Title investigative ophthalmology & visual science
Publication Year Start




PMID- 28727885
OWN - NLM
STAT- MEDLINE
DA  - 20170720
DCOM- 20170728
LR  - 20170728
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Linking)
VI  - 58
IP  - 9
DP  - 2017 Jul 01
TI  - Sustained Activation of the Unfolded Protein Response Induces Cell Death in
      Fuchs' Endothelial Corneal Dystrophy.
PG  - 3697-3707
LID - 10.1167/iovs.16-21023 [doi]
AB  - Purpose: The unfolded protein response (UPR) is believed to play a role in the
      pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this 
      study was to investigate whether unfolded proteins accumulate in the corneal
      endothelium in FECD and if they are involved in triggering cell death. Methods:
      Descemet's membranes with corneal endothelial cells (CECs) were obtained during
      keratoplasty, and expression of aggresomes, type 1 collagen, fibronectin, and
      agrin was evaluated. Endoplasmic reticulum (ER) stress of immortalized human CECs
      from non-FECD subjects and from FECD patients (iHCEC and iFECD, respectively)
      were evaluated. The effect of MG132-mediated aggresome formation on the UPR and
      intrinsic pathway and the effect of mitochondrial damage on UPR were also
      examined. The effect of CHOP knockdown on the ER stress-mediated intrinsic
      pathway was also evaluated. Results: Aggresome formation was higher in iFECD than
      in iHCEC and was colocalized with type 1 collagen, fibronectin, and agrin. GRP78,
      phosphorylated IRE1, PERK, and CHOP showed higher activation in iFECD than in
      iHCEC. MG132-mediated aggresome formation upregulated ER stress sensors, the
      mitochondrial membrane potential drop, cytochrome c release to the cytoplasm, and
      activation of caspase-9 and -3. By contrast, staurosporine-mediated mitochondrial
      damage did not induce ER stress. Knockdown of CHOP attenuated the ER
      stress-induced cleavage of caspase-9, which is caused by intrinsic pathway
      activation. Conclusions: Excessive synthesis of extracellular matrix proteins
      induced unfolded protein accumulation in FECD. Prolonged ER stress-mediated cell 
      death, occurring via the intrinsic apoptotic signaling pathway, therefore might
      be associated with the pathogenesis of FECD.
FAU - Okumura, Naoki
AU  - Okumura N
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
FAU - Kitahara, Miu
AU  - Kitahara M
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
FAU - Okuda, Hirokazu
AU  - Okuda H
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
FAU - Hashimoto, Keisuke
AU  - Hashimoto K
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
FAU - Ueda, Emi
AU  - Ueda E
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
FAU - Nakahara, Makiko
AU  - Nakahara M
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
FAU - Kinoshita, Shigeru
AU  - Kinoshita S
AD  - Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto
      Prefectural University of Medicine, Kyoto, Japan.
FAU - Young, Robert D
AU  - Young RD
AD  - Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff
      University, Cardiff, United Kingdom.
FAU - Quantock, Andrew J
AU  - Quantock AJ
AD  - Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff
      University, Cardiff, United Kingdom.
FAU - Tourtas, Theofilos
AU  - Tourtas T
AD  - Department of Ophthalmology, University of Erlangen-Nurnberg, Erlangen, Germany.
FAU - Schlotzer-Schrehardt, Ursula
AU  - Schlotzer-Schrehardt U
AD  - Department of Ophthalmology, University of Erlangen-Nurnberg, Erlangen, Germany.
FAU - Kruse, Friedrich
AU  - Kruse F
AD  - Department of Ophthalmology, University of Erlangen-Nurnberg, Erlangen, Germany.
FAU - Koizumi, Noriko
AU  - Koizumi N
AD  - Department of Biomedical Engineering, Faculty of Life and Medical Sciences,
      Doshisha University, Kyotanabe, Japan.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Agrin)
RN  - 0 (Collagen Type I)
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Fibronectins)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (molecular chaperone GRP78)
SB  - IM
MH  - Agrin/metabolism
MH  - *Apoptosis
MH  - Cells, Cultured
MH  - Collagen Type I/metabolism
MH  - Descemet Membrane/metabolism/pathology
MH  - Endoplasmic Reticulum/metabolism/pathology
MH  - Endothelium, Corneal/*metabolism
MH  - Extracellular Matrix Proteins/*metabolism
MH  - Fibronectins/metabolism
MH  - Fuchs' Endothelial Dystrophy/metabolism/*pathology
MH  - Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Membrane Potential, Mitochondrial/physiology
MH  - Middle Aged
MH  - Oxidative Stress
MH  - Protein Aggregation, Pathological/metabolism/*pathology
MH  - Real-Time Polymerase Chain Reaction
MH  - Unfolded Protein Response/*physiology
EDAT- 2017/07/21 06:00
MHDA- 2017/07/29 06:00
CRDT- 2017/07/21 06:00
AID - 2645788 [pii]
AID - 10.1167/iovs.16-21023 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2017 Jul 1;58(9):3697-3707. doi:
      10.1167/iovs.16-21023.