Kesteven, S. H. | Search bioRxiv

bioRxiv2025

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 of Piezo1 from 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-Piezo1 KO mice exhibited impaired cardiac relaxation due to altered cellular Ca2+ handling kinetics. Young adult Piezo1 KO 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, where Piezo1 expression 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 conditional Piezo1 KO 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.

biophysics↗

bioRxiv2020

Cardiac Gq receptors and calcineurin activation are not required for the hypertrophic response to mechanical left ventricular pressure overload

RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial. ObjectiveTo determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload. Methods and ResultsTransgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signalling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI+/-) mice and absent in homozygous (GqI-/-) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and -skeletal actin (-SA) was increased 48 hours after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and -SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKII{delta} levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels. ConclusionCardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but are not required for LVH induced by mechanical pressure overload (TAC); the latter is mediated by activation of the CaMKII-HDAC4-MEF2 pathway.

molecular biology↗