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Cardiovascular Research Advance Access originally published online on February 11, 2008
Cardiovascular Research 2008 78(3):533-545; doi:10.1093/cvr/cvn030
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

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

Kwang-Ming Fang1,2,{dagger}, An-Sheng Lee3,{dagger}, Ming-Jai Su3, Chien-Liang Lin1, Chung-Liang Chien4,* and Mei-Lin Wu1,*

1 Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
2 Department of Dental Laboratory Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan
3 Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
4 Institutes of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

* Corresponding author. Tel: +886 2 23123456 ext. 8242; fax: +886 2 23224330. E-mail address: meilin{at}ntu.edu.tw

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 mycoyte 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 Ca2+ and Na+ overload. AA caused sustained cytosolic [Na+]cyt and [Ca2+]cyt overload, resulting in mitochondrial [Na+]m and [Ca2+]m overload, which induced caspase-3-mediated apoptosis. Similar apoptotic effects were seen using Na+ ionophore cocktail/Ca2+-free medium, which induced [Na+]cyt and [Na+]m, but not [Ca2+]cyt and [Ca2+]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.

KEYWORDS Arachidonic acid; Mitochondrial Na+; Apoptosis

Time for primary review: 30 days

{dagger} The first two authors have contributed equally to this work.


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