Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts.
Actins
/ genetics
Adult
Animals
Cell Nucleus
/ metabolism
Cells, Cultured
Fibroblasts
/ cytology
Humans
Male
Mechanotransduction, Cellular
Membrane Proteins
/ antagonists & inhibitors
Microscopy, Fluorescence
Myofibroblasts
/ cytology
Neoplasm Proteins
/ antagonists & inhibitors
Promoter Regions, Genetic
RNA Interference
RNA, Small Interfering
/ metabolism
Rats
Transforming Growth Factor beta1
/ pharmacology
fibrosis
focal adhesion
mechanical stress
mechanosensation
nuclear shuttling
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
17 12 2020
17 12 2020
Historique:
received:
16
11
2020
revised:
11
12
2020
accepted:
14
12
2020
entrez:
22
12
2020
pubmed:
23
12
2020
medline:
22
6
2021
Statut:
epublish
Résumé
We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis.
Identifiants
pubmed: 33348602
pii: cells9122702
doi: 10.3390/cells9122702
pmc: PMC7766948
pii:
doi:
Substances chimiques
ACTA2 protein, human
0
Actins
0
FERMT3 protein, human
0
Membrane Proteins
0
Neoplasm Proteins
0
RNA, Small Interfering
0
Transforming Growth Factor beta1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : 210820
Pays : Canada
Organisme : CIHR
ID : 286920
Pays : Canada
Organisme : CIHR
ID : 375597
Pays : Canada
Organisme : CIHR
ID : MOP-86535
Pays : Canada
Organisme : CIHR
ID : MOP-106625
Pays : Canada
Organisme : CIHR
ID : 246193
Pays : Canada
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