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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 11, 2008
Cardiovascular Research, 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

An-Sheng Lee1,* and Chung-Liang Chien2

1 Institutes of Pharmacology College of Medicine, National Taiwan University, Taipei, Taiwan
2 Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

* Correspondence Dr. An-Sheng Lee Institute of Pharmacology College of Medicine National Taiwan University No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan Fax: +886-2-23224330 Tel: +886-2-23123456 ext 8242 E-mail: bfang{at}ctust.edu.tw

Aim: 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-ischemia 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.

Conclusions: 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


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