A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells.
Atherosclerosis
/ pathology
CRISPR-Cas Systems
Calcium Signaling
Endothelial Cells
/ metabolism
Humans
Inflammation
Kruppel-Like Transcription Factors
/ genetics
MAP Kinase Kinase 5
MAP Kinase Kinase Kinase 2
MAP Kinase Kinase Kinase 3
Mitochondria
/ metabolism
Mitogen-Activated Protein Kinase 7
/ genetics
Reactive Oxygen Species
Stress, Mechanical
Journal
The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356
Informations de publication
Date de publication:
04 07 2022
04 07 2022
Historique:
received:
28
09
2021
revised:
15
03
2022
accepted:
11
05
2022
entrez:
13
6
2022
pubmed:
14
6
2022
medline:
16
6
2022
Statut:
ppublish
Résumé
Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3-MEK5-ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK-MEK5-ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease.
Identifiants
pubmed: 35695893
pii: 213278
doi: 10.1083/jcb.202109144
pmc: PMC9198948
pii:
doi:
Substances chimiques
KLF2 protein, human
0
Kruppel-Like Transcription Factors
0
Reactive Oxygen Species
0
Mitogen-Activated Protein Kinase 7
EC 2.7.11.24
MAP Kinase Kinase Kinase 2
EC 2.7.11.25
MAP Kinase Kinase Kinase 3
EC 2.7.11.25
MAP3K2 protein, human
EC 2.7.11.25
MAP3K3 protein, human
EC 2.7.11.25
MAP Kinase Kinase 5
EC 2.7.12.2
MAP2K5 protein, human
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : R01 HL75092
Pays : United States
Organisme : European Research Council
ID : ERC-CoG 647057
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL075092
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS063973
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 Coon et al.
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