Piezo1 as a Novel Link Between Fibrosis and Inflammation in Atrial Fibrillation

Ramona Emig (Freiburg im Breisgau)1, M. Koch (Freiburg im Breisgau)1, P. Iaconianni (Freiburg im Breisgau)1, K. Kollmar (Freiburg im Breisgau)1, C. Walz (Freiburg im Breisgau)1, T. Prinz (Freiburg)2, A. Lother (Freiburg)2, P. Kohl (Freiburg im Breisgau)1, U. Ravens (Freiburg im Breisgau)1, R. Peyronnet (Freiburg im Breisgau)1

1Universitäts-Herzzentrum Freiburg - Bad Krozingen Institut für Experimentelle Kardiovaskuläre Medizin Freiburg im Breisgau, Deutschland; 2Institute of Experimental and Clinical Pharmacology and Toxicology Freiburg, Deutschland


Atrial fibrillation (AF), one of the most prevalent cardiac arrhythmias in humans, is accompanied by atrial dilatation, fibrotic remodelling and inflammation. It is well-established that stretch can trigger structural (and functional) remodelling, and that tissue fibrosis contributes to changes in cardiac tissue mechanics which is sensed and responded to by cardiac cells. Atrial inflammation in response to dilatation is often regarded as an additional trigger for the development of fibrosis in AF. How mechanical stimulation of fibroblasts affects inflammatory cells, and whether that may alter tissue mechanics is under-investigated.

The cation non-selective, stretch-activated channel Piezo1, which is expressed at higher levels in atrial fibroblasts isolated from patients with AF, compared to patients in sinus rhythm,1 is a functionally relevant mechanosensor in these cells and contributes to the control of interleukin (IL) 6 secretion. Using RNA sequencing, we identified that reducing the expression level of Piezo1 decreases the expression of additional pro-inflammatory cytokines, including monocyte/macrophage chemoattractant protein-1 (MCP-1) and IL-8. As soluble signalling molecules, these may contribute to indirect mechanical modulation of inflammatory processes, such as immune cell recruitment from the circulation.

To assess the capacity of human atrial fibroblasts to affect immunologically relevant processes in a paracrine Piezo1-dependent manner, we performed a series of in vitro co-culture experiments. Using transient knock-down or overexpression of Piezo1 in human atrial fibroblasts, we found that the expression level of Piezo1 correlated with the ability of fibroblasts to attract THP-1 monocytes in transwell migration assays. Higher Piezo1 expression led to 36% higher THP-1 migration toward fibroblasts while Piezo1 down regulation led to 33% lower THP-1 migration (3 independent experiments). Similar observations were made for primary human neutrophils (50% higher and 47% lower migration towards fibroblasts for Piezo1 up- and down-regulation respectively). The migration of THP-1 monocytes was promoted by MCP-1, while that of neutrophils – by IL-8. Additionally, Piezo1-dependent secretion of IL-6 in human atrial fibroblasts affected the expression of intercellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells.

Taken together, these data indicate that Piezo1 expression in human atrial fibroblasts may affect immune cell recruitment from the circulation by collectively acting on endothelial cells, monocytes and neutrophils via paracrine signalling. As Piezo1 is upregulated in AF, this might be novel mechanism, linking mechanical alterations in atrial tissue to enhanced atrial inflammation, contributing to disease progression. Our hypothesis-generating observations will be followed up with the aim of exploring new strategies for the development of therapeutics to slow down or stop adverse remodelling in AF. 

1 Jakob D and Klesen A et al.,. Journal of Molecular and Cellular Cardiology 2021/158: 49-62.

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