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A beneficial role of cardiac P2X₄ receptors in heart failure: rescue of the calsequestrin overexpression model of cardiomyopathy

¹Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, Connecticut 06030; ²Krannert Institute of Cardiology, Indiana University School of Medicine, Indiana 46202; and ³University of Utah School of Medicine, Salt Lake City, Utah 84132

Submitted 3 February 2004 ; accepted in final form 1 May 2004

The P2X₄ purinergic receptor (P2X₄R) is a ligand-gated ion channel. Its activation by extracellular ATP results in Ca²⁺ influx. Transgenic cardiac overexpression of the human P2X₄ receptor showed an in vitro phenotype of enhanced basal contractility. The objective here was to determine the in vivo cardiac physiological role of this receptor. Specifically, we tested the hypothesis that this receptor plays an important role in modulating heart failure progression. Transgenic cardiac overexpression of canine calsequestrin (CSQ) showed hypertrophy, heart failure, and premature death. Crossing the P2X₄R mouse with the CSQ mouse more than doubled the lifespan (182 ± 91 days for the binary CSQ/P2X₄R mouse, n = 35) of the CSQ mouse (71.3 ± 25.4 days, n = 50, P < 0.0001). The prolonged survival in the binary CSQ/P2X₄R mouse was associated with an improved left ventricular weight-to-body weight ratio and a restored -adrenergic responsiveness. The beneficial phenotype of the binary mouse was not associated with any downregulation of the CSQ level but correlated with improved left ventricular developed pressure and ±dP/dt. The enhanced cardiac performance was manifested in young binary animals and persisted in older animals. The increased contractility likely underlies the survival benefit from P2X₄ receptor overexpression. An increased expression or activation of this receptor may represent a new approach in the therapy of heart failure.

cardiac failure; contraction; isoproterenol; purines; adenine nucleotide

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