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Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts

Godbout, Elena
Son, Dong Ok
Hume, Stephanie
Boo, Stellar
Sarrazy, Vincent
Kapus, Andras
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Published in Cells. 2020, vol. 9, no. 12, 2702
Abstract 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.
Keywords Actins/genetics/metabolismAdultAnimalsCell Nucleus/metabolismCellsCulturedFibroblasts/cytology/metabolismHumansMaleMechanotransductionCellularMembrane Proteins/antagonists & inhibitors/genetics/metabolismMicroscopyFluorescenceMyofibroblasts/cytology/drug effects/metabolismNeoplasm Proteins/antagonists & inhibitors/genetics/metabolismPromoter RegionsGeneticRNA InterferenceRNASmall Interfering/metabolismRatsTransforming Growth Factor beta1/pharmacology
PMID: 33348602
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Research groups Etudes et traitement de l'hépatite C et B (554)
Migration cellulaire (645)
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GODBOUT, Elena et al. Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts. In: Cells, 2020, vol. 9, n° 12, p. 2702. doi: 10.3390/cells9122702 https://archive-ouverte.unige.ch/unige:153893

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Deposited on : 2021-08-17

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