Popdc knock out results in sick sinus syndrome

Abstract

Purpose: The Popeye domain containing (Popdc) family of three novel muscle-restricted genes (Popdc1-3) are evolutionarily conserved and expressed prominently within the cardiac conduction system and the purpose of this study was to delineate the role of Popdc1 in sinus node pacemaking using transgenic mice lacking the Popdc1 gene (Popdc1-/-). Methods: Male Popdc1-/- mice (C57BL/6J background) of 5.5 months age were used. The study followed "Principles of laboratory animal care" (NIH Publication no. 85-23 revised 1985) and is in accordance with the United Kingdom Animals (Scientific Procedures) Act, 1986. The ECG in conscious animals was recorded via telemetry at rest, during and after physiological stress (swim) or catecholamine treatment. In addition, extracellular potentials were recorded from isolated sinus node preparations. Results: At 5.5 months, Popdc1-/- mice showed reduced body weight compared to wild type (WT) mice (27±2 vs. 32±1 g; P<0.05). Popdc1-/- mice displayed no obvious pathological cardiac phenotype at rest, but developed an unusual bradycardia with sinus pauses in response to swim stress or catecholamine treatment. In isolated sinus node preparations from Popdc1-/- mice, the intrinsic sinus rate was not significantly different from that in preparations from WT mice (363±16 vs. 387±20 bpm). β-adrenergic stimulation with the agonist isoprenaline (5 nM) induced a positive chronotropic effect (456±18 bpm) in WT preparations, but this effect was blunted (378±9 bpm; P<0.05 vs. WT) in Popdc1-/- preparations. In the presence of isoprenaline (5, 15 and 50 nM), extrasystoles, bursts and sinus pauses were observed, but these three phenotypes were either more prevalent or occurred exclusively in Popdc1-/- preparations. This abberant pacemaking in the Popdc-/- mice could be the result of a disturbance of either the voltage- or Ca2+-clock pacemaker mechanisms. Blocking the pacemaker current I(f) (major component of voltage-clock) with 2 mM Cs(+) induced a bradycardia that was equally pronounced in the WT (265±25 vs. 385±20 bpm at control; P<0.05) and Popdc1-/- (220±14 vs. 355±5 bpm at control; P<0.05) preparations, indicating no change in I(f). However, isoprenaline (50 nM) failed to evoke extrasystoles, bursts and sinus pauses when the Ca2+-clock was rendered dysfunctional with 2 μM ryanodine suggesting a role for the Ca2+-clock in the isoprenaline induced bradycardia phenotype. Conclusions: Popdc1-/- is essential for stress-mediated modulation of cardiac pacemaking. Ca2+-clock proteins are likely mediators of the β-adrenergic stimulation induced sinus bradycardia phenotype.