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1 The Center for Cardiology and Cardiovascular Biology, University of Connecticut, Farmington, CT, USA
2 Indiana University School of Medicine, Krannert Institute of Cardiology, Indianapolis, IN, USA
3 University of Utah School of Medicine, Salt Lake City, Utah, USA
* To whom correspondence should be addressed. E-mail: bliang{at}uchc.edu.
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, it 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 into 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.
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