Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway
Date
2005
Authors
Engelbrecht A.-M.
Engelbrecht P.
Genade S.
Niesler C.
Page C.
Smuts M.
Lochner A.
Journal Title
Journal ISSN
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Abstract
The mechanisms by which long-chain dietary polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease are largely unknown. The present study determines the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the response of neonatal rat cardiomyocytes to simulated ischaemia (SI) and reperfusion (R). Myocytes isolated from 1-2 day old Wistar rat hearts were cultured with or without EPA or ARA and exposed to 1 h SI followed by 30 minutes reperfusion. Apoptosis was evaluated by caspase-3 activation, poly-(ADP-ribose) polymerase (PARP) cleavage and nuclear condensation. EPA (20μM) and ARA (20μM) significantly inhibited caspase-3 activation and PARP-cleavage and reduced the apoptotic index during reperfusion. Both fatty acids significantly increased ERK phosphorylation and decreased p38 phosphorylation during reperfusion. The mechanism of action of ARA on the MAPKs was further investigated with okadaic acid (to inhibit serine-threonine phosphatases) and orthovanadate (to inhibit tyrosine phosphatases). Vanadate, but not okadaic acid, significantly reduced ARA-induced inhibition of p38 phosphorylation, suggesting the involvement a tyrosine phosphatase during SI/R. Mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity phosphatase, was targeted and a significant induction of MKP-1 by ARA and EPA was observed. It was demonstrated for the first time that EPA and ARA protect neonatal cardiac myocytes from ischaemia/reperfusion-induced apoptosis through activation of ERK as well as induction of a dual-specific phosphatase, causing dephosphorylation of the pro-apoptotic kinase, p38. The cardioprotective effects of EPA and ARA could also be demonstrated on the functional recovery of isolated perfused hearts subjected to global ischemia. © 2005 Elsevier Ltd. All rights reserved.
Description
Keywords
arachidonic acid, caspase 3, icosapentaenoic acid, mitogen activated protein kinase, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, okadaic acid, orthovanadic acid, phosphatase, polyunsaturated fatty acid, synaptophysin, animal cell, animal model, apoptosis, article, cell isolation, cell viability, controlled study, dephosphorylation, drug effect, drug mechanism, enzyme activation, enzyme degradation, enzyme inhibition, enzyme phosphorylation, enzyme specificity, fatty acid analysis, heart muscle cell, heart muscle ischemia, heart protection, muscle fiber culture, newborn, nonhuman, priority journal, rat, reperfusion injury, signal transduction, Animals, Animals, Newborn, Apoptosis, Arachidonic Acid, Cells, Cultured, Eicosapentaenoic Acid, MAP Kinase Signaling System, Myocardial Reperfusion Injury, Myocardium, Myocytes, Cardiac, Rats, Rats, Wistar, Animalia, Rattus norvegicus
Citation
Journal of Molecular and Cellular Cardiology
39
6
39
6