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(Circulation. 2001;103:2395.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Increased Release of Arachidonic Acid and Eicosanoids in Iron-Overloaded Cardiomyocytes

Rafael Mattera, PhD; Gregory P. Stone, BA; Nael Bahhur, BA; Yuri A. Kuryshev, PhD

From Rammelkamp Center for Education and Research, MetroHealth Medical Center (R.M., G.P.S., N.B., Y.A.K.) and Department of Medicine (R.M.), Case Western Reserve University School of Medicine, Cleveland, Ohio.

Correspondence to Rafael Mattera, PhD, Cell Biology and Metabolism Branch, NICHD, Building 18T, Room 101, Bethesda, MD 20892. E-mail matterar{at}helix.nih.gov

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.

Methods and Results—Neonatal rat ventricular myocytes (NRVMs) cultured for 72 hours in the presence of 80 µg/mL ferric ammonium citrate displayed an increased rate of AA release, both under resting conditions and after stimulation with agonists such as [Sar¹]Ang II. Although iron treatment did not affect overall incorporation of [³H]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 A₂ and C. Iron-overloaded cardiomyocytes also displayed increased production of eicosanoids and induction of cyclooxygenase-2 after stimulation with interleukin-1.

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.

Key Words: cardiomyopathy • prostaglandins • signal transduction • myocytes • iron