Shear stress induces a longitudinal Ca2+ wave via autocrine activation of P2Y1 purinergic signalling in rat atrial myocytes

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Abstract

Atrial myocytes are exposed to shear stress during the cardiac cycle and haemodynamic disturbance. In response, they generate a longitudinally propagating global Ca2+ wave. Here, we investigated the cellular mechanisms underlying the shear stress-mediated Ca2+ wave, using two-dimensional confocal Ca2+ imaging combined with a pressurized microflow system in single rat atrial myocytes. Shear stress of ˜16 dyn cm−2 for 8 s induced ˜1.2 aperiodic longitudinal Ca2+ waves (˜79 μm s−1) with a delay of 0.2−3 s. Pharmacological blockade of ryanodine receptors (RyRs) or inositol 1,4,5-trisphosphate receptors (IP3Rs) abolished shear stress-induced Ca2+ wave generation. Furthermore, in atrial myocytes from type 2 IP3R (IP3R2) knock-out mice, shear stress failed to induce longitudinal Ca2+ waves. The phospholipase C (PLC) inhibitor U73122, but not its inactive analogue U73343, abolished the shear-induced longitudinal Ca2+ wave. However, pretreating atrial cells with blockers for stretch-activated channels, Na+−Ca2+ exchanger, transient receptor potential melastatin subfamily 4, or nicotinamide adenine dinucleotide phosphate oxidase did not suppress wave generation under shear stress. The P2 purinoceptor inhibitor suramin, and the potent P2Y1 receptor antagonist MRS 2179, both suppressed the Ca2+ wave, whereas the P2X receptor antagonist, iso-PPADS, did not alter it. Suppression of gap junction hemichannels permeable to ATP or extracellular application of ATP-metabolizing apyrase inhibited the wave. Removal of external Ca2+ to enhance hemichannel opening facilitated the wave generation. Our data suggest that longitudinally propagating, regenerative Ca2+ release through RyRs is triggered by P2Y1–PLC–IP3R2 signalling that is activated by gap junction hemichannel-mediated ATP release in atrial myocytes under shear stress.

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