P2 receptors in human heart: Upregulation of P2X6 in patients undergoing heart transplantation, interaction with TNFα and potential role in myocardial cell death

Cristina Banfi, Silvia Ferrario, Ombretta De Vincenti, Stefania Ceruti, Marta Fumagalli, Alessia Mazzola, Nadia D'Ambrosi, Cinzia Volontè, Pasquale Fratto, Ettore Vitali, Geoffrey Burnstock, Elena Beltrami, Alessandro Parolari, Gianluca Polvani, Paolo Biglioli, Elena Tremoli, Maria P. Abbracchio

Research output: Contribution to journalArticlepeer-review

Abstract

ATP acts as a neurotransmitter via seven P2X receptor-channels for Na + and Ca2+, and eight G-protein-coupled P2Y receptors. Despite evidence suggesting roles in human heart, the map of myocardial P2 receptors is incomplete, and their involvement in chronic heart failure (CHF) has never received adequate attention. In left myocardia from five to nine control and 5-12 CHF subjects undergoing heart transplantation, we analyzed the full repertoire of P2 receptors and of 10 "orphan" P2Y-like receptors. All known P2Y receptors (i.e. P2Y1,2,4,6,11,12,13,14) and two P2Y-like receptors (GPR91 and GPR17) were detected in all subjects. All known P2X1-7 receptors were also detected; of these, only P2X6 was upregulated in CHF, as confirmed by quantitative real time-PCR. The potential significance of this change was studied in primary cardiac fibroblasts freshly isolated from young pigs. Exposure of cardiac fibroblasts to ATP or its hydrolysis-resistant-analog benzoylATP induced apoptosis. TNFα (a cytokine implicated in CHF progression) exacerbated cell death. Similar effects were induced by ATP and TNFα in a murine cardiomyocytic cell line. In cardiac fibroblasts, TNFα inhibited the downregulation of P2X6 mRNA associated to prolonged agonist exposure, suggesting that, by preventing ATP-induced P2X6 desensitization, TNFα may abolish a defense mechanism meant at avoiding Ca2+ overload and, ultimately, Ca 2+-dependent cell death. This may provide a basis for P2X6 upregulation in CHF. In conclusion, we provide the first characterization of P2 receptors in the human heart and suggest that the interaction between TNFα and the upregulated P2X6 receptor may represent a novel pathogenic mechanism in CHF.

Original languageEnglish
Pages (from-to)929-939
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number6
DOIs
Publication statusPublished - Dec 2005

Keywords

  • Apoptosis
  • Cytokines
  • Gene expression
  • Heart failure
  • Receptors

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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