en
Scientific article
Open access
English

Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts

Published inCells, vol. 9, no. 12, 2702
Publication date2020
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/metabolism
  • Adult
  • Animals
  • Cell Nucleus/metabolism
  • Cells
  • Cultured
  • Fibroblasts/cytology/metabolism
  • Humans
  • Male
  • Mechanotransduction
  • Cellular
  • Membrane Proteins/antagonists & inhibitors/genetics/metabolism
  • Microscopy
  • Fluorescence
  • Myofibroblasts/cytology/drug effects/metabolism
  • Neoplasm Proteins/antagonists & inhibitors/genetics/metabolism
  • Promoter Regions
  • Genetic
  • RNA Interference
  • RNA
  • Small Interfering/metabolism
  • Rats
  • Transforming Growth Factor beta1/pharmacology
Citation (ISO format)
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
Main files (1)
Article (Published version)
Identifiers
ISSN of the journal2073-4409
124views
71downloads

Technical informations

Creation07/02/2021 6:51:00 PM
First validation07/02/2021 6:51:00 PM
Update time03/16/2023 1:03:24 AM
Status update03/16/2023 1:03:23 AM
Last indexation02/12/2024 12:08:43 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack