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KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: Implication for Cerebral Cavernous Malformation disease

KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: Implication for Cerebral Cavernous Malformation disease

Authors :
Simona Delle Monache
Stefania Pizzimenti
Adriano Angelucci
Vincenzo Nicola Talesa
Martina Daga
Andrea Perrelli
Paola Cassoni
Lorenza Trabalzini
Eliana Trapani
Giuseppina Barrera
Luca Goitre
Saverio Francesco Retta
Cinzia Antognelli
Source :
Free Radical Biology & Medicine
Publication Year :
2018

Abstract

KRIT1 (CCM1) is a disease gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease of proven genetic origin affecting 0.3–0.5% of the population. Previously, we demonstrated that KRIT1 loss-of-function is associated with altered redox homeostasis and abnormal activation of the redox-sensitive transcription factor c-Jun, which collectively result in pro-oxidative, pro-inflammatory and pro-angiogenic effects, suggesting a novel pathogenic mechanism for CCM disease and raising the possibility that KRIT1 loss-of-function exerts pleiotropic effects on multiple redox-sensitive mechanisms. To address this possibility, we investigated major redox-sensitive pathways and enzymatic systems that play critical roles in fundamental cytoprotective mechanisms of adaptive responses to oxidative stress, including the master Nrf2 antioxidant defense pathway and its downstream target Glyoxalase 1 (Glo1), a pivotal stress-responsive defense enzyme involved in cellular protection against glycative and oxidative stress through the metabolism of methylglyoxal (MG). This is a potent post-translational protein modifier that may either contribute to increased oxidative molecular damage and cellular susceptibility to apoptosis, or enhance the activity of major apoptosis-protective proteins, including heat shock proteins (Hsps), promoting cell survival. Experimental outcomes showed that KRIT1 loss-of-function induces a redox-sensitive sustained upregulation of Nrf2 and Glo1, and a drop in intracellular levels of MG-modified Hsp70 and Hsp27 proteins, leading to a chronic adaptive redox homeostasis that counteracts intrinsic oxidative stress but increases susceptibility to oxidative DNA damage and apoptosis, sensitizing cells to further oxidative challenges. While supporting and extending the pleiotropic functions of KRIT1, these findings shed new light on the mechanistic relationship between KRIT1 loss-of-function and enhanced cell predisposition to oxidative damage, thus providing valuable new insights into CCM pathogenesis and novel options for the development of preventive and therapeutic strategies.<br />Graphical abstract Schematic models representing adaptive redox responses associated with KRIT1 loss-of-function. KRIT1 loss-of-function causes a persistent activation of the redox-sensitive transcription factors c-Jun and Nrf2 and consequent upregulation of downstream targets, including cycloxygenase-2 (COX-2), heme oxygenase-1 (HO-1) and glyoxalase 1 (GLO1). While the c-Jun/COX-2 axis promotes pro-oxidant and pro-inflammatory effects, the Nrf2/HO-1 and Nrf2/GLO1 pathways mediate adaptive antioxidant responses that counteract these effects by limiting ROS* and MG intracellular accumulation, thus contributing to reduce a vicious cycle of oxidative stress and providing an adaptive defense for long term cell survival. However, this sustained adaptive redox homeostasis occurs at the expense of other cytoprotective mechanisms, including the MG-dependent formation of cytoprotective AP-Hsp70 and AP-Hsp27 protein adducts, leading to enhanced cell susceptibility to oxidative DNA damage and apoptosis, and sensitizing cells to additional stressful insults. Inter-individual differences in Nrf2-mediated adaptive defense mechanisms might influence susceptibility to CCM disease onset and progression. *The generic ROS term refers to O2•−and H2O2as well as to putative secondary oxidative products that might be implicated without certainty.fx1<br />Highlights • KRIT1 loss causes a chronic adaptive redox response based on the JNK-Nrf2-Glo1 axis. • Phospho-JNK, Nrf2 and Glo1 are upregulated in endothelial cells lining human CCMs. • Defective autophagy contributes to the sustained upregulation of the Nrf2-Glo1 axis. • Nrf2-Glo1 upregulation causes a drop of AP-modified Hsp70 and Hsp27 proteins. • Sustained Nrf2-Glo1 activation sensitizes cells to oxidative stress and apoptosis.

Subjects

Subjects :
0301 basic medicine
Nuclear factor erythroid 2-related factor 2 (Nrf2)
Hemangioma, Cavernous, Central Nervous System
PTM, post-translational modification
Redox signaling
HSP27 Heat-Shock Proteins
Apoptosis
ICH, intracerebral hemorrhage
AGEs, advanced glycation end-products
medicine.disease_cause
Nrf2, nuclear factor erythroid 2-related factor 2
Biochemistry
hBMEC, human brain microvascular endothelial cells
Hsp, heat-shock protein
Central Nervous System Neoplasms
Mice
Antioxidant defense
Homeostasis
Cerebrovascular disease
KRIT1 Protein
Cells, Cultured
Mice, Knockout
chemistry.chemical_classification
education.field_of_study
Lactoylglutathione Lyase
Brain
Pyruvaldehyde
Cell biology
Keap1, Kelch-like ECH-associated protein 1
NVU, neurovascular unit
Heme oxygenase-1 (HO-1)
HO-1, Heme oxygenase-1
Oxidation-Reduction
medicine.medical_specialty
BBB, blood-brain barrier
NF-E2-Related Factor 2
TUNEL, TdT-mediated dUTP nick-end labeling
Population
Oxidative phosphorylation
Biology
Cerebral Cavernous Malformations
CNS, central nervous system
Article
Adaptive redox homeostasis
03 medical and health sciences
ROS, reactive oxygen species
Downregulation and upregulation
SOD, superoxide dismutase
Internal medicine
Heat shock protein
Physiology (medical)
Autophagy
CCM, Cerebral Cavernous Malformation
medicine
Animals
Humans
EndMT, endothelial-to-mesenchymal transition
HSP70 Heat-Shock Proteins
CCM1/KRIT1
ARE, antioxidant-response element
AP, argpyrimidine (Nẟ-(5-hydroxy-4,6-dimethylpyrimidine-2-yl)-l-ornithine)
Glo1, Glyoxalase 1
education
JNK, c-Jun NH2-terminal kinase
Casp-3, Caspase-3
KRIT1, Krev interaction trapped 1
Reactive oxygen species
Oxidative DNA damage and apoptosis
Glyoxalase 1 (Glo1)
c-Jun
Endothelial Cells
COX-2, cycloxygenase-2
Argpyrimidine-modified heat-shock proteins
Oxidative stress
MEF, mouse embryonic fibroblast
030104 developmental biology
Endocrinology
chemistry
Mutation
Cyt c, cytochrome c
MG, methylglyoxal
Protein Processing, Post-Translational

Details

Language :
English
Database :
OpenAIRE
Journal :
Free Radical Biology & Medicine
Accession number :
edsair.doi.dedup.....9626ca3388471d5ac6e4cae96d0dfe5e