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 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.

Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

“…Moreover, they demonstrated an attenuated progression of the pathological cardiac hypertrophy in cardiac-specific Piezo1 knockdown mice and in cardiomyocytes, but also a reduction in fibrotic remodeling. These achievements were recently confirmed by Ze-Yan Yu and collaborators [ 112 ]. In their article, they provide evidence about Piezo1 and TRPM4 physical interaction, which is responsible for the activation of the signaling cascade resulting in pathological hypertrophy.…”

“…Among the analyzed channels, TRPC6, TRPV1, and TRPV4, expressed by CFs, were considered. Therefore, TRP channels likely act downstream of other channels responsible for the mechanical stimulation signaling, such as Piezo1, as already proposed for TRPM4 [ 89 , 112 ] and TRPV4 channels [ 113 , 114 ]. Lastly, the role of Piezo1 as an upstream regulator of potassium-selective TREK-1 was highlighted [ 102 ], as previously mentioned.…”

“…The same group had previously demonstrated the role of TRPM4 as a positive regulator of left ventricular hypertrophy induced by pressure overload [ 89 ]; however, only recently were able to address the TRPM4 channel activity to a downstream effect of Piezo1. Therefore, in this last work [ 112 ], Piezo1 was confirmed as the primary mechanotransducer that initiates the pressure overload response via TRPM4.…”

“…Despite several studies about Piezo1 in the cardiomyocyte [ 19 , 20 , 112 , 128 ], however, only recently have reports been started to focus on its role in cardiac fibroblasts. Many efforts are now focusing on possible fibroblasts Piezo1-mediated heart dysfunctions, and due to the well-known role of these cells in fibrosis, it is supposed that promising and helpful new Piezo1-based mechanisms could be revealed.…”

Piezo1 as a force-through-membrane sensor in red blood cells

“…In larger cell types, co-localization of Piezo1 with other channels might be necessary to elicit a functional coupling of ion fluxes. In rat ventricular myocytes, for example, Piezo1 has recently been shown, by diffraction-limited confocal microscopy, to co-localize with transient receptor melastatin (TRPM4) channels (Yu et al 2022).…”