Deletion of PIEZO1 in adult cardiomyocytes accelerates cardiac aging and causes premature death

Mechanosensitive PIEZO1 channels have emerged as key transducers of mechanical forces in the cardiovascular system. In cardiomyocytes, we previously showed that PIEZO1 decodes mechanical cues driving pressure-overload induced hypertrophy. However, conflicting reports exist on the influence of PIEZO1 on baseline cardiac function. Here we show that conditional deletion ofPiezo1from cardiomyocytes in adult mice results in premature mortality. The hearts from these mice exhibited signs of accelerated aging, including elevated markers of the senescence associated secretory phenotype, with significant blunting of the normal cardiac hypertrophic response to aging, associated with a reduction in the activation of the pro-hypertrophic Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Functionally, aged-Piezo1KO mice exhibited impaired cardiac relaxation due to altered cellular Ca²⁺handling kinetics. Young adultPiezo1KO mice exhibited a normal resting heart rate but developed significant progressive sinus bradycardia and cardiac fibrotic remodelling with aging, which was most prominent in the right atrium, wherePiezo1expression is highest in the healthy heart. Mechanistically, loss of PIEZO1 was associated with a marked reduction in the anti-fibrotic molecule, atrial natriuretic peptide (ANP). Moreover,in vivo,ANP release instigated by atrial stretch was markedly blunted in conditionalPiezo1KO mice, providing a plausible and long sought-after mechanism for the link between mechanical stretch and ANP release. Taken together, our data show that PIEZO1 is a crucial homeostatic molecule during cardiac aging, enabling adaptation to an aging tissue microenvironment.