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Am J Physiol Gastrointest Liver Physiol 287: G518-G526, 2004. First published April 15, 2004; doi:10.1152/ajpgi.00514.2003
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HORMONES AND SIGNALING

ANP-induced decrease of iron regulatory protein activity is independent of HO-1 induction

Alexandra K. Kiemer,1,2 Anke C. Förnges,1,2 Kostas Pantopoulos,3 Manfred Bilzer,2 Bill Andriopoulos,3 Tobias Gerwig,1,2 Silke Kenngott,2 Alexander L. Gerbes,2 and Angelika M. Vollmar1

1Department of Pharmacy, Center of Drug Research, 2Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany; and 3Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2

Submitted 10 December 2003 ; accepted in final form 9 April 2004

Atrial natriuretic peptide (ANP)-preconditioned livers are protected from ischemia-reperfusion injury. ANP-treated organs show increased expression of heme oxygenase (HO)-1. Because HO-1 liberates bound iron, the aim of our study was to determine whether ANP affects iron regulatory protein (IRP) activity and, thus, the levels of ferritin. Rat livers were perfused with Krebs-Henseleit buffer [±ANP, 8-bromo-cGMP (8-Br-cGMP), and tin protoporphyrin, 20 min], stored in University of Wisconsin solution (4°C, 24 h), and reperfused (120 min). IRP activity was assessed by gel-shift assays, and ferritin, IRP phosphorylation, and PKC localization were assessed by Western blot. Control livers displayed decreased IRP activity at the end of ischemia but no change in ferritin content during ischemia and reperfusion. ANP-pretreated livers showed reduced IRP activity, an effect mimicked by 8-Br-cGMP. Ferritin levels were increased in ANP-pretreated organs. Simultaneous perfusion of livers with ANP and tin protoporphyrin did not reduce ANP-induced action, arguing against a role for HO-1 in changes in IRP activity. ANP and 8-Br-cGMP decreased membrane localization of PKC-{alpha} and PKC-{epsilon}, but this modulation of PKC seems unrelated to inhibition of IRP binding. This work shows the cGMP-mediated attenuation of IRP binding activity by ANP, which results in increased hepatic ferritin levels. This change in IRPs is independent of ANP-induced HO-1 and reduced PKC activation.

cGMP; ischemia-reperfusion injury; heat-shock proteins; hepatoprotection; hormonal preconditioning


Address for reprint requests and other correspondence: A. K. Kiemer, The Scripps Research Institute, Dept. of Molecular and Experimental Medicine, MEM131, 10550 North Torrey Pines Rd., La Jolla, CA 92037 (E-mail: kiemer{at}scripps.edu)






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