A beneficial role of cardiac P2X 4 receptors in heart failure: Rescue of the calsequestrin overexpression model of cardiomyopathy

Alexander Yang, Dimitry Sonin, Larry Jones, William H. Barry, Bruce T. Liang

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The P2X 4 purinergic receptor (P2X 4R) is a ligand-gated ion channel. Its activation by extracellular ATP results in Ca 2+ influx. Transgenic cardiac overexpression of the human P2X 4 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 P2X 4R mouse with the CSQ mouse more than doubled the lifespan (182 ± 91 days for the binary CSQ/P2X 4R mouse, n = 35) of the CSQ mouse (71.3 ± 25.4 days, n = 50, P < 0.0001). The prolonged survival in the binary CSQ/P2X 4R mouse was associated with an improved left ventricular weight-to-body weight ratio and a restored β-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 P2X 4 receptor overexpression. An increased expression or activation of this receptor may represent a new approach in the therapy of heart failure.

Original languageEnglish (US)
Pages (from-to)H1096-H1103
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number3 56-3
DOIs
StatePublished - Sep 1 2004

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Keywords

  • Adenine nucleotide
  • Cardiac failure
  • Contraction
  • Isoproterenol
  • Purines

ASJC Scopus subject areas

  • Physiology

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