Increased release of arachidonic acid and eicosanoids in iron-overloaded cardiomyocytes.
BACKGROUND
Patients with transfusional iron overload may develop a life-limiting cardiomyopathy. The sensitivity of lipid-metabolizing enzymes to peroxidative injury, as well as the reported effects of arachidonic acid (AA) and metabolites on cardiac rhythm, led us to hypothesize that iron-overloaded cardiomyocytes display alterations in the release of AA and prostaglandins.


RESULTS
Neonatal rat ventricular myocytes (NRVMs) cultured for 72 hours in the presence of 80 microgram/mL ferric ammonium citrate displayed an increased rate of AA release, both under resting conditions and after stimulation with agonists such as [Sar(1)]Ang II. Although iron treatment did not affect overall incorporation of [(3)H]AA into NRVM phospholipids, it caused a 2-fold increase in the distribution of precursor in phosphatidylcholine species, with a proportional decrease in phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine. Increased release of AA in iron-overloaded NRVMs was reduced by the diacylglycerol lipase inhibitor RHC80267 but was largely insensitive to inhibitors of phospholipases A(2) and C. Iron-overloaded cardiomyocytes also displayed increased production of eicosanoids and induction of cyclooxygenase-2 after stimulation with interleukin-1alpha.


CONCLUSIONS
Iron overload enhances AA release and incorporation of AA into phosphatidylcholine, as well as cyclooxygenase-2 induction and eicosanoid production, in NRVMS: The effects of AA and metabolites on cardiomyocyte rhythmicity suggest a causal connection between these signals and electromechanical alterations in iron-overload-induced cardiomyopathy.
Mattera
R
R
Rammelkamp Center for Education and Research, MetroHealth Medical Center, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. matterar@helix.nih.gov
Stone
G P
GP
Bahhur
N
N
Kuryshev
Y A
YA
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism*; D005260:Female; D005290:Ferric Compounds / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D011247:Pregnancy; D011453:Prostaglandins / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium
D015777:Eicosanoids; D005290:Ferric Compounds; D010743:Phospholipids; D011453:Prostaglandins; D000644:Quaternary Ammonium Compounds; C027053:angiotensin II, Sar(1)-Car(4)-; D014316:Tritium; D000804:Angiotensin II; D016718:Arachidonic Acid; D007501:Iron; C013531:ferric ammonium citrate