Piezo1 is the cardiac mechanosensor that initiates the cardiomyocyte hypertrophic response to pressure overload in adult mice

Abstract Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel key to activation of Ca 2+ /calmodulin-dependent kinase II (CaMKII)-reliant hypertrophic signaling pathway after pressure overload, but TRPM4 neither stretch-activated nor -permeable. Here we show that Piezo1, which both -permeable, the mechanosensor transduces increased myocardial forces into chemical signal initiates via close physical interaction TRPM4. Cardiomyocyte-specific deletion Piezo1 in adult mice prevented CaMKII inhibited response: residual was associated calcineurin absence its usual inhibition by activated CaMKII. upregulation sodium–calcium exchanger changes other handling proteins overload. These findings establish as cardiomyocyte instigates therapeutic target.