Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice

Author:

Bartoli FionaORCID,Evans Elizabeth L.,Blythe Nicola M.,Stewart Leander,Chuntharpursat-Bon EulashiniORCID,Debant MarjolaineORCID,Musialowski Katie E.,Lichtenstein LaeticiaORCID,Parsonage Gregory,Futers T. Simon,Turner Neil A.ORCID,Beech David J.ORCID

Abstract

PIEZO1 is a subunit of mechanically-activated, nonselective cation channels. Gain-of-function PIEZO1 mutations are associated with dehydrated hereditary stomatocytosis (DHS), a type of anaemia, due to abnormal red blood cell function. Here, we hypothesised additional effects on the heart. Consistent with this hypothesis, mice engineered to contain the M2241R mutation in PIEZO1 to mimic a DHS mutation had increased cardiac mass and interventricular septum thickness at 8–12 weeks of age, without altered cardiac contractility. Myocyte size was greater and there was increased expression of genes associated with cardiac hypertrophy (Anp, Acta1 and β-MHC). There was also cardiac fibrosis, increased expression of Col3a1 (a gene associated with fibrosis) and increased responses of isolated cardiac fibroblasts to PIEZO1 agonism. The data suggest detrimental effects of excess PIEZO1 activity on the heart, mediated in part by amplified PIEZO1 function in cardiac fibroblasts.

Funder

British Heart Foundation

Wellcome Trust

Publisher

MDPI AG

Subject

General Medicine

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