NDLI: Mechanically activated Piezo1 channels of cardiac fibroblasts stimulate p38 mitogen-activated protein kinase activity and interleukin-6 secretion.

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Mechanically activated Piezo1 channels of cardiac fibroblasts stimulate p38 mitogen-activated protein kinase activity and interleukin-6 secretion.

Content Provider	Europe PMC
Author	Blythe, Nicola M. Muraki, Katsuhiko Ludlow, Melanie J. Stylianidis, Vasili Gilbert, Hamish T. J. Evans, Elizabeth L. Cuthbertson, Kevin Foster, Richard Swift, Joe Li, Jing Drinkhill, Mark J. van Nieuwenhoven, Frans A. Porter, Karen E. Beech, David J. Turner, Neil A.
Copyright Year	2019
Abstract	Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however, its role in the heart is poorly understood. Cardiac fibroblasts help preserve myocardial integrity and play a key role in regulating its repair and remodeling following stress or injury. Here we investigated Piezo1 expression and function in cultured human and mouse cardiac fibroblasts. RT-PCR experiments confirmed that Piezo1 mRNA in cardiac fibroblasts is expressed at levels similar to those in endothelial cells. The results of a Fura-2 intracellular Ca2+ assay validated Piezo1 as a functional ion channel that is activated by its agonist, Yoda1. Yoda1-induced Ca2+ entry was inhibited by Piezo1 blockers (gadolinium and ruthenium red) and was reduced proportionally by siRNA-mediated Piezo1 knockdown or in murine Piezo1+/− cells. Results from cell-attached patch clamp recordings on human cardiac fibroblasts established that they contain mechanically activated ion channels and that their pressure responses are reduced by Piezo1 knockdown. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation increases both mRNA levels and protein secretion of IL-6, a pro-hypertrophic and profibrotic cytokine, in a Piezo1-dependent manner. Moreover, Piezo1 knockdown reduced basal IL-6 expression from cells cultured on softer collagen-coated substrates. Multiplex kinase activity profiling combined with kinase inhibitor experiments and phosphospecific immunoblotting established that Piezo1 activation stimulates IL-6 secretion via the p38 mitogen-activated protein kinase downstream of Ca2+ entry. In summary, cardiac fibroblasts express mechanically activated Piezo1 channels coupled to secretion of the paracrine signaling molecule IL-6. Piezo1 may therefore be important in regulating cardiac remodeling.
ISSN	00219258
Volume Number	294
PubMed Central reference number	PMC6873183
Issue Number	46
PubMed reference number	31586031
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1074/jbc.RA119.009167
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2019-10-04
Publisher Place	U.S.A.
Access Restriction	Open
Rights License	Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license. © 2019 Blythe et al.
Subject Keyword	ion channel calcium p38 MAPK mitogen-activated protein kinase (MAPK) IL-6 fibroblast heart mechanotransduction patch clamp signal transduction cardiac fibroblast
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry

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