Chronic Hemodynamic Overload of the Atria is an Important Factor for Shear Signaling Remodeling in Rat Hearts

Abstract

Hemodynamic disturbances induced by hypertension, heart failure, and valve diseases lead atrial fibrillation. We have previously shown that shear stress induces proarrhythmic Ca2+ waves via connexin43 (Cx43) hemichannel opening, and that ATP release through the Cx43, in turn, activates P2Y1 receptors (P2Y1Rs) and P2X4 receptors (P2X4Rs) in rat atrial myocytes. To understand cellular mechanism for mechanically-induced atrial arrhythmia and role of shear signaling in this pathogenesis, we compared atrial shear signaling between sham-operated rats and the rats subjected to prolonged transverse aortic constriction (TAC). Atrial cell hypertrophy with higher fractional shortening and dilation of atrial chamber were observed at 5 weeks (wk) after TAC surgery. On 4-month (mon) after TAC surgery, more severe dilation in atrium with lower fractional shortening was detected. Whole-cell patch clamp studies revealed that shear-induced nonselective cation currents that are mediated by P2X4Rs (about 50%) and Cx43 (about 20%), were enhanced with hypertrophy, but they were no longer enhanced during atrial failure. Total Cx43 proteins and phosphorylated Cx43 at its ser-368 residue were gradually increased by TAC, which was consistent with larger shear-induced NMDG+ currents in TAC rat atrial myocytes. P2X4R expression increased in 5-wk-TAC atrial cells, but decreased in 4-mon-TAC atrial cells. On the other hand, P2Y1R-dependent longitudinal Ca2+ waves and P2Y1R expression were significantly increased by 4-mon-TAC. Our data suggest that Cx43-P2 receptor-mediated shear signaling is significantly altered by the progress of atrial dilation and volume overload, and that biphasic changes in P2X4R function and expression versus TAC duration may play a role in the progression from hypertrophy to failure in atrium subjected to aortic stenosis and increased afterload.