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- Title
Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts.
- Authors
Godbout, Elena; Son, Dong Ok; Hume, Stephanie; Boo, Stellar; Sarrazy, Vincent; Clément, Sophie; Kapus, Andras; Wehrle-Haller, Bernhard; Bruckner-Tuderman, Leena; Has, Cristina; Hinz, Boris
- 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.
- Subjects
MYOFIBROBLASTS; FOCAL adhesions; CELL contraction; CARDIAC patients; MICROBEADS; FIBROBLASTS
- Publication
Cells (2073-4409), 2020, Vol 9, Issue 12, p2702
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells9122702