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

Ze-Yan Yu; Hutao Gong; Scott Kesteven; Yang Guo; Jianxin Wu; Jinyuan Vero Li; Delfine Cheng; Zijing Zhou; Siiri E Iismaa; Xenia Kaidonis; Robert M Graham; Charles D Cox; Michael P Feneley; Boris Martinac

doi:10.1038/s44161-022-00082-0

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

Nat Cardiovasc Res. 2022 Jun;1(6):577-591. doi: 10.1038/s44161-022-00082-0. Epub 2022 Jun 13.

Authors

Ze-Yan Yu^{1

2

3}, Hutao Gong^{1

2

3}, Scott Kesteven^{2

3}, Yang Guo^{1

2

3}, Jianxin Wu¹, Jinyuan Vero Li¹, Delfine Cheng^{1

3}, Zijing Zhou¹, Siiri E Iismaa^{1

3}, Xenia Kaidonis^{1

3}, Robert M Graham^{1

3}, Charles D Cox^{1

3}, Michael P Feneley^{4

5

6}, Boris Martinac^{7

8}

Affiliations

¹ Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
² Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
³ St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁴ Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia. [email protected].
⁵ St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. [email protected].
⁶ Department of Cardiology, St Vincent's Hospital, Sydney, New South Wales, Australia. [email protected].
⁷ Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia. [email protected].
⁸ St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. [email protected].

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 is key to activation of a Ca²⁺/calmodulin-dependent kinase II (CaMKII)-reliant hypertrophic signaling pathway after pressure overload, but TRPM4 is neither stretch-activated nor Ca²⁺-permeable. Here we show that Piezo1, which is both stretch-activated and Ca²⁺-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signaling via a close physical interaction with TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice prevented activation of CaMKII and inhibited the hypertrophic response: residual hypertrophy was associated with calcineurin activation in the absence of its usual inhibition by activated CaMKII. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and changes in other Ca²⁺ handling proteins after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, and as a potential therapeutic target.