Free fatty acids act as endogenous ionophores, resulting in Na+ and Ca2+ influx and myocyte apoptosis

Cardiovasc Res. 2008 Jun 1;78(3):533-45. doi: 10.1093/cvr/cvn030. Epub 2008 Feb 11.

Abstract

Aims: Disturbances in lipid metabolism have been suggested to play an important role in myocardial damage. Marked accumulation of free fatty acids (FFAs), including arachidonic acid (AA), palmitic acid, oleic acid, and linoleic acid, occurs during post-ischaemia and reperfusion (post-I/R). Possible cellular mechanisms of AA/FFAs-induced myocyte apoptosis were investigated.

Methods and results: In neonatal rat ventricular myocytes, AA/FFAs activate a novel non-selective cation conductance (NSCC), resulting in both intracellular Ca(2+) and Na(+) overload. AA caused sustained cytosolic [Na(+)](cyt) and [Ca(2+)](cyt) overload, resulting in mitochondrial [Na(+)](m) and [Ca(2+)](m) overload, which induced caspase-3-mediated apoptosis. Similar apoptotic effects were seen using Na(+) ionophore cocktail/Ca(2+)-free medium, which induced [Na(+)](cyt) and [Na(+)](m), but not [Ca(2+)](cyt) and [Ca(2+)](m) overload. Electron microscopy showed that inhibition of [Na(+)](m) overload prevented disruption of the mitochondrial membrane, showing that [Na(+)](m) overload is an important upstream signal in AA- and FFA-induced myocyte apoptosis.

Conclusion: AA and FFAs, which accumulate in the myocardium during post-I/R, may therefore act as naturally occurring endogenous ionophores and contribute to the myocyte death seen during post-I/R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis*
  • Arachidonic Acid / metabolism
  • Calcium / metabolism*
  • Caspase 3 / metabolism
  • Cytochromes c / metabolism
  • Cytosol / metabolism
  • Fatty Acids, Nonesterified / metabolism*
  • Female
  • Guinea Pigs
  • In Vitro Techniques
  • Ionophores / metabolism*
  • Linoleic Acid / metabolism
  • Male
  • Membrane Potentials
  • Microscopy, Confocal
  • Microscopy, Electron
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / ultrastructure
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Swelling
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / ultrastructure
  • Oleic Acid / metabolism
  • Palmitic Acid / metabolism
  • Patch-Clamp Techniques
  • Sodium / metabolism*
  • Time Factors

Substances

  • Fatty Acids, Nonesterified
  • Ionophores
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Arachidonic Acid
  • Oleic Acid
  • Palmitic Acid
  • Cytochromes c
  • Linoleic Acid
  • Sodium
  • Caspase 3
  • Calcium