ATP acts as a survival signal and prevents the mineralization of aortic valve

J Mol Cell Cardiol. 2012 May;52(5):1191-202. doi: 10.1016/j.yjmcc.2012.02.003. Epub 2012 Feb 16.

Abstract

Calcific aortic valve disease (CAVD) is a disorder related to progressive mineralization of valvular tissue that is a leading cause of heart disease. Thus far, there is no medical treatment to prevent the mineralization of aortic valves. It is generally thought that pathologic mineralization is linked to apoptosis of vascular cells. However, the role of apoptosis during mineralization as well as the survival signals for valvular interstitial cells (VICs), the main cellular component of aortic valves, remains to be identified. Here, through several lines of evidence, we show that bioavailability of extracellular ATP is a signal which determines survival or apoptosis of VICs and, in doing so, plays a major role in the development of CAVD. Specifically, in CAVD and in VIC cultures undergoing mineralization, we found a high level of the ectonucleotidase ENPP1. In addition, a genetic polymorphism in the intron 9 of the ENPP1 gene was associated with CAVD in a case-control cohort as well as with mRNA expression levels of ENPP1 in aortic valves. A high level of ENPP1 in CAVD promoted apoptosis-mediated mineralization of VICs by depleting the extracellular pool of ATP. We then documented that release of ATP by VICs promoted cell survival via the P2Y(2) receptor and the PI3K/Akt signaling pathway. Hence, our results show that level of ENPP1 modulates extracellular concentration of ATP, which is an important survival signal for VICs. These findings may help to develop novel pharmacological treatment for CAVD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / physiology*
  • Aortic Valve / metabolism
  • Aortic Valve / pathology*
  • Apoptosis
  • Calcinosis / metabolism*
  • Calcinosis / pathology
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / pathology
  • Case-Control Studies
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Gene Expression Profiling
  • Genetic Association Studies
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Phosphates / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoric Diester Hydrolases / genetics*
  • Phosphoric Diester Hydrolases / metabolism
  • Polymorphism, Single Nucleotide
  • Pyrophosphatases / genetics*
  • Pyrophosphatases / metabolism
  • Receptors, Purinergic P2X / genetics
  • Receptors, Purinergic P2X / metabolism
  • Receptors, Purinergic P2Y / genetics
  • Receptors, Purinergic P2Y / metabolism
  • Signal Transduction
  • Sodium-Phosphate Cotransporter Proteins, Type III / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type III / metabolism
  • Tissue Array Analysis

Substances

  • Phosphates
  • Receptors, Purinergic P2X
  • Receptors, Purinergic P2Y
  • SLC20A1 protein, human
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • Adenosine Triphosphate
  • Phosphatidylinositol 3-Kinases
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases