Fig. 8: Schematic of the Piezo1-dependent signaling pathway that drives LVH secondary to pressure overload.

Piezo1 is the cardiomyocyte mechanotransducer that converts the increased mechanical forces (either through membrane tension or force conveyed by cytoskeletal elements or integrins) secondary to pressure overload into Ca²⁺ entry into the cell. This increases local [Ca²⁺], resulting in TRPM4 activation. The Na⁺-permeable TRPM4 activity increases local [Na⁺], driving the NCX to extrude Na⁺, resulting in less extrusion of Ca²⁺ or Ca²⁺ entry via NCX. This leads to a high-amplitude increase in local [Ca²⁺]. Calmodulin responds to this high-amplitude Ca²⁺ stimulus through the lower-affinity Ca²⁺ binding site at its N-lobe, which then preferentially activates CaMKIIδ and thus stimulates the CaMKII-HDAC4-MEF2 pathway to induce LVH⁶. In contrast, calcineurin is activated preferentially by low-amplitude Ca²⁺ signaling via Gq-coupled receptors and calmodulin, and calcineurin activation is strongly inhibited by activated CaMKIIδ. These two mechanisms explain the strong functional segregation of the two hypertrophic signaling pathways despite their common dependence on activation via Ca²⁺/calmodulin. ECM, extracellular matrix; CaM, calmodulin.