Different roles of P2X4- and P2Y1-receptors in the atrial pathogenesis during prolonged pressure overload.

Abstract

Pressure overload (PO) involve increase in interstitial fluid shear in cardiac muscle during cardiac cycles due to detachment of myocytes from the extracellular matrix and myocyte slippage. However, the effects of shear stress on cardiac muscle and their pathophysiological roles are poorly understood. We have recently discovered that shear stress induces global Ca2+ waves via activation of P2 purinergic receptors in atrial myocytes by ATP released from the cells, and that this ATP release is mediated by connexin 43 (Cx43) gap junction hemichannels. In this study, we investigated role of shear stress signaling in PO-induced atrial remodeling and failure. We used a transverse aortic constriction (TAC) rat model to increase afterload and examined shear stress responses and remodeling of their signaling molecules during the development of pathological phenotypes by progressive TAC. After 5-week TAC, atrial dimension was enlarged with ventricular hypertrophy, which was followed by severe atrial dilation as well as ventricular failure at long-term (>20-week) TAC. Atrial myocytes were enlarged following 5-week TAC, which was maintained during more prolonged TAC. In the 5-week-TAC left atrial (LA) cells, ATP release was increased with no changes in Cx43 expression and in Cx43 hemichannel-mediated dye (calcein) flux. At this stage, however, function (cation current) of P2X4 receptor (P2X4R) and their protein expressions were largely enhanced. In failed LA cells, reduction in the Cx43 expression and smaller Cx43 hemichannel-mediated dye flux were observed. In failed LA myocytes, shear-induced longitudinal Ca2+ waves that were mediated by P2Y1 receptor (P2Y1R), were enhanced with higher P2Y1R expression. The opposite changes in the shear-induced responses mediated by P2X4R and P2Y1R and in their expressions suggest that P2X4R and P2Y1R may play beneficial and harmful role, respectively, in the PO-dependent atrial pathogenesis.