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.